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Bibliography on: Taste-Aversion Learning

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 31 Jul 2021 at 01:54 Created: 

Taste-Aversion Learning

The notion of "conditioned taste aversions" refers to animals' ability to preferentially associate taste with illness, despite the passage of a significant time between ingestion and illness. When first described, this pattern seemed so at variance with the tenets of classical learning theory that one early reviewer claimed "results like that are no more likely than birdshit in a cuckoo clock." Now, however, the reality of the phenomenon is well established and has demonstrated relevance in practical areas ranging from rodent control to chemotherapy.

Created with PubMed® Query: "taste aversion" or "bait shyness" NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-07-30

Dantzer R (2021)

Love and fear in the times of sickness.

Comprehensive psychoneuroendocrinology, 6:.

Sickness induced by gastrointestinal malaise or by microbial pathogens is more than a private experience. Sick individuals share their illness within their social environment by communicating their sickness to others. In turn, recipients of the communication respond with appropriate behavioral adaptations. Avoidance of sick individuals and the events associated with their sickness is advantageous for members of the group. However, these responses can conflict with the need for comfort or social support expressed by sick individuals. There is evidence that the relationship between the sick individual and its social environment involves neurobiological mechanisms that are similar to those that mediate social bonding. Despite their commonality the feelings of love and fear/disgust that are associated with the sociality of sickness have thus far been neglected by mainstream affective neuroscience.

RevDate: 2021-07-29

Wu CW, Ou CY, Yu YH, et al (2021)

Involvement of the ventral tegmental area but not periaqueductal gray matter in the paradoxical rewarding and aversive effects of morphine.

Behavioral neuroscience pii:2021-69213-001 [Epub ahead of print].

The paradoxical effects of reward and aversion with abused drugs may interact to produce drug addiction, which is the so-called paradoxical effect hypothesis of abused drugs. However, there is no research examining how the ventral tegmental area (VTA) or periaqueductal gray matter (PAG) regulates morphine's paradoxical effect of reward and aversion. The present study addresses this issue, utilizing a high concentration of N-methyl-D-aspartic acid (NMDA) via injections to destroy the VTA or the PAG. Moreover, the study employed the new "pre- and postassociation" experimental paradigm (2010) to test whether the simultaneous rewarding and aversive effects of morphine can be affected by an NMDA lesion in the VTA or the PAG. The results indicated that the NMDA lesion of the VTA simultaneously reduced morphine-induced conditioned suppression of saccharin solution intake in conditioned taste aversion (CTA) and morphine-induced spent time in the preference compartment in conditioned place preference (CPP), whereas the PAG lesion did not change either measure. Thus, the VTA, but not the PAG, appears to contribute to the paradoxical effect reward in CPP and aversion in CTA induced by morphine. The VTA's involvement in morphine-induced CTA aversion and CPP reward supports the paradoxical effect hypothesis of abused drugs. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

RevDate: 2021-06-21

Wang YC, Chiu WC, Cheng CN, et al (2021)

Examination of neuroinflammatory cytokine interleukin-1 beta expression in the medial prefrontal cortex, amygdala, and hippocampus for the paradoxical effects of reward and aversion induced by morphine.

Neuroscience letters pii:S0304-3940(21)00454-7 [Epub ahead of print].

A growing body of evidence has shown that abused drugs could simultaneously induce the paradoxical effect-reward and aversion. Moreover, the medial prefrontal cortex (mPFC), amygdala, and hippocampus were involved in this paradoxical effect by abused drugs. However, no research examined whether neuroinflammatory changes in the mPFC [including cingulate cortex area 1 (Cg1); prelimbic cortex (PrL); infralimbic cortex (IL)], basolateral amygdala, and hippocampus [e.g., CA1, CA2, CA3, and dentate gyrus (DG)] after morphine-induced reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA). The results showed that after morphine administration, the consumption of a 0.1% saccharin solution decreased; the mean time spent in the morphine-paired side compartment of the CPP box increased, indicating that morphine simultaneously induced the paradoxical effects of reward and aversion. The PrL and IL of the mPFC, the BLA of the amygdala, the CA1, CA2, CA3, and DG of the hippocampus but not the Cg1 presented hyperactive IL-1β expression in response to morphine's aversion and reward. The mPFC, amygdala, and hippocampus may appear neuroinflammation activity following morphine-induced paradoxical effect-reward in CPP and aversion in CTA. The present data may provide a better understanding of the relationship between neuroinflammation and morphine addiction.

RevDate: 2021-05-30

Rivi V, Batabyal A, Juego K, et al (2021)

To eat or not to eat: a Garcia effect in pond snails (Lymnaea stagnalis).

Journal of comparative physiology. A, Neuroethology, sensory, neural, and behavioral physiology [Epub ahead of print].

Taste aversion learning is universal. In animals, a single presentation of a novel food substance followed hours later by visceral illness causes animals to avoid that taste. This is known as bait-shyness or the Garcia effect. Humans demonstrate this by avoiding a certain food following the development of nausea after ingesting that food ('Sauce Bearnaise effect'). Here, we show that the pond snail Lymnaea stagnalis is capable of the Garcia effect. A single 'pairing' of a novel taste, a carrot slurry followed hours later by a heat shock stressor (HS) is sufficient to suppress feeding response elicited by carrot for at least 24 h. Other food tastes are not suppressed. If snails had previously been exposed to carrot as their food source, the Garcia-like effect does not occur when carrot is 'paired' with the HS. The HS up-regulates two heat shock proteins (HSPs), HSP70 and HSP40. Blocking the up-regulation of the HSPs by a flavonoid, quercetin, before the heat shock, prevented the Garcia effect in the snails. Finally, we found that snails exhibit Garcia effect following a period of food deprivation but the long-term memory (LTM) phenotype can be observed only if the animals are tested in a food satiated state.

RevDate: 2021-05-18

Zhong W, NA Darmani (2021)

The HCN Channel Blocker ZD7288 Induces Emesis in the Least Shrew (Cryptotis parva).

Frontiers in pharmacology, 12:647021.

Subtypes (1-4) of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in the central and peripheral nervous systems, as well as the cells of smooth muscles in many organs. They mainly serve to regulate cellular excitability in these tissues. The HCN channel blocker ZD7288 has been shown to reduce apomorphine-induced conditioned taste aversion on saccharin preference in rats suggesting potential antinausea/antiemetic effects. Currently, in the least shew model of emesis we find that ZD7288 induces vomiting in a dose-dependent manner, with maximal efficacies of 100% at 1 mg/kg (i.p.) and 83.3% at 10 µg (i.c.v.). HCN channel subtype (1-4) expression was assessed using immunohistochemistry in the least shrew brainstem dorsal vagal complex (DVC) containing the emetic nuclei (area postrema (AP), nucleus tractus solitarius and dorsal motor nucleus of the vagus). Highly enriched HCN1 and HCN4 subtypes are present in the AP. A 1 mg/kg (i.p.) dose of ZD7288 strongly evoked c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem DVC, but not in the in the enteric nervous system in the jejunum, suggesting a central contribution to the evoked vomiting. The ZD7288-evoked c-Fos expression exclusively occurred in tryptophan hydroxylase 2-positive serotonin neurons of the dorsal vagal complex, indicating activation of serotonin neurons may contribute to ZD7288-induced vomiting. To reveal its mechanism(s) of emetic action, we evaluated the efficacy of diverse antiemetics against ZD7288-evoked vomiting including the antagonists/inhibitors of: ERK1/2 (U0126), L-type Ca2+ channel (nifedipine); store-operated Ca2+ entry (MRS 1845); T-type Ca2+ channel (Z944), IP3R (2-APB), RyR receptor (dantrolene); the serotoninergic type 3 receptor (palonosetron); neurokinin 1 receptor (netupitant), dopamine type 2 receptor (sulpride), and the transient receptor potential vanilloid 1 receptor agonist, resiniferatoxin. All tested antiemetics except sulpride attenuated ZD7288-evoked vomiting to varying degrees. In sum, ZD7288 has emetic potential mainly via central mechanisms, a process which involves Ca2+ signaling and several emetic receptors. HCN channel blockers have been reported to have emetic potential in the clinic since they are currently used/investigated as therapeutic candidates for cancer therapy related- or unrelated-heart failure, pain, and cognitive impairment.

RevDate: 2021-06-14

Har-Paz I, Arieli E, A Moran (2021)

ApoE4 attenuates cortical neuronal activity in young behaving apoE4 rats.

Neurobiology of disease, 155:105373.

The E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD-related neuropathology. Understanding these primary dysfunctions is vital for the early detection of AD and the development of therapeutic strategies. Recently we reported impaired extra-hippocampal memory in young apoE4 mice, a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we tested the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 (hApoE4) and wildtype rats expressing rat apoE (rAE), before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young hApoE4 rats showed impaired CTA learning, consistent with our previous results in target-replacement apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Further taste coding analyses at the single neuron and ensemble levels revealed that GC neurons of the hApoE4 group correctly classified tastes, but were unable to undergo plasticity to support learning. These results suggest that apoE4 impacts brain excitability and plasticity early in life that may act as an initiator for later AD pathologies.

RevDate: 2021-04-30

Yiannakas A, Kolatt Chandran S, Kayyal H, et al (2021)

Parvalbumin interneuron inhibition onto anterior insula neurons projecting to the basolateral amygdala drives aversive taste memory retrieval.

Current biology : CB pii:S0960-9822(21)00523-6 [Epub ahead of print].

Memory retrieval refers to the fundamental ability of organisms to make use of acquired, sometimes inconsistent, information about the world. Although memory acquisition has been studied extensively, the neurobiological mechanisms underlying memory retrieval remain largely unknown. Conditioned taste aversion (CTA) is a robust associative paradigm, through which animals can be trained to express aversion toward innately appetitive tastants. The anterior insula (aIC) is indispensable in the ability of mammals to retrieve associative information regarding tastants that have been previously linked with gastric malaise. Here, we show that CTA memory retrieval promotes cell-type-specific activation in the aIC. Using chemogenetic tools in the aIC, we found that CTA memory acquisition requires activation of excitatory neurons and inhibition of inhibitory neurons, whereas retrieval necessitates activation of both excitatory and inhibitory aIC circuits. CTA memory retrieval at the aIC activates parvalbumin (PV) interneurons and increases synaptic inhibition onto activated pyramidal neurons projecting to the basolateral amygdala (aIC-BLA). Unlike innately appetitive taste memory retrieval, CTA retrieval increases synaptic inhibition onto aIC-BLA-projecting neurons that is dependent on activity in aIC PV interneurons. PV aIC interneurons coordinate CTA memory retrieval and are necessary for its dominance when conflicting internal representations are encountered over time. The reinstatement of CTA memories following extinction is also dependent on activation of aIC PV interneurons, which increase the frequency of inhibition onto aIC-BLA-projecting neurons. This newly described interaction of PV and a subset of excitatory neurons can explain the coherency of aversive memory retrieval, an evolutionary pre-requisite for animal survival.

RevDate: 2021-06-08

Urrieta E, ML Escobar (2021)

Metaplastic regulation of neocortical long-term depression in vivo is sensitive to distinct phases of conditioned taste aversion.

Neurobiology of learning and memory, 182:107449.

Metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Accumulated evidence has proposed that metaplasticity contributes to network function and cognitive processes such as learning and memory. In this regard, it has been observed that training in several behavioral tasks modifies the possibility to induce subsequent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). For instance, our previous studies have shown that conditioned taste aversion (CTA) training prevents the induction of in vivo LTP in the projection from the basolateral nucleus of the amygdala to the insular cortex (BLA-IC). Likewise, we reported that extinction of CTA allows induction but not maintenance of LTP in the same pathway. Besides, we showed that it is possible to express in vivo low-frequency stimulation LTD in the BLA-IC projection and that its induction prior to CTA training facilitates the extinction of this task. However, until now, little is known about the participation of LTD on metaplastic processes. The present study aimed to analyze whether CTA training modifies the expression of in vivo LTD in the BLA-IC projection. To do so, animals received low-frequency stimulation to induce IC-LTD 48 h after CTA training. Our results show that CTA training occludes the subsequent induction of LTD in the BLA-IC pathway in a retrieval-dependent manner. These findings reveal that CTA elicits a metaplastic regulation of long-lasting changes in the IC synaptic strength, as well as that specific phases of learning differentially take part in adjusting the expression of synaptic plasticity in neocortical regions.

RevDate: 2021-06-10
CmpDate: 2021-06-10

de Brugada I, González F, Cándido A, et al (2021)

Contextual control of the retardation of flavour aversion learning by preexposure to the unconditioned stimulus: Acquisition or retrieval deficit?.

Behavioural processes, 188:104394.

Two experiments, using rats as the subjects, and flavour aversion learning with an injection of lithium chloride (LiCl) as the unconditioned stimulus (US), examined the effects of a context shift between phases of the procedure on the retardation of learning produced by preexposure to the US. Experiment 1 showed that the US-preexposure effect (the reduction in the size of the conditioned aversion) was not attenuated when the animals were given both preexposure to the US and the conditioning procedure in a novel context but received the test phase in a different context (the home cages). Experiment 2 showed that, after degrading the injection cues-illness association by interpolating saline injections between LiCl preexposures, the US-preexposure effect was attenuated when there was a context shift between preexposure and conditioning, but that the context shift was without effect when it occurred between conditioning and test. These results are consistent with the proposal that US preexposure obtained in this procedure has its effect by interfering with the formation of the target association; they provide no support for the suggestion that the effect depends on interference at the test stage.

RevDate: 2021-05-31

Osorio-Gómez D, Bermúdez-Rattoni F, KR Guzmán-Ramos (2021)

Cortical neurochemical signaling of gustatory stimuli and their visceral consequences during the acquisition and consolidation of taste aversion memory.

Neurobiology of learning and memory, 181:107437.

The insular cortex (IC) has a crucial role in taste recognition memory, including conditioned taste aversion (CTA). CTA is a learning paradigm in which a novel taste stimulus (CS) is associated with gastric malaise (US), inducing aversion to the CS in future encounters. The role of the IC in CTA memory formation has been extensively studied. However, the functional significance of neurotransmitter release during the presentation of taste stimuli and gastric malaise-inducing agents remains unclear. Using microdialysis in free-moving animals, we evaluated simultaneous changes in glutamate, norepinephrine and dopamine release in response to the presentation of an innate appetitive or aversive gustatory novel stimulus, as well as after i.p. administration of isotonic or hypertonic gastric malaise-inducing solutions. Our results demonstrate that the presentation of novel stimuli, regardless of their innate valence, induces an elevation of norepinephrine and dopamine. Administration of a gastric malaise inducing agent (LiCl) promotes an elevation of glutamate regardless of its concentration. In comparison, norepinephrine release is related to the LiCl concentration and its equimolar NaCl control. Additionally, we evaluated their functional role on short and long-term taste aversion memory. Results indicate that the blockade of noradrenergic β1,2 receptors in the IC spares CTA acquisition and memory consolidation. In contrast, blockade of dopamine D1/D5 receptors impaired CTA consolidation, whereas the NMDA receptor blockade impedes both acquisition and consolidation of CTA. These results suggest that dopaminergic and noradrenergic release are related to the salience of conditioned taste stimuli. However, only cortical D1/D5 dopaminergic activity, but not the noradrenergic β1,2 activity, is involved in the acquisition and consolidation of taste memory formation. Additionally, glutamatergic activity signals visceral distress caused by LiCl administration and activates NMDA receptors necessary for the acquisition and consolidation of long-lasting taste aversion memory.

RevDate: 2021-04-13

Kotańska M, Mika K, Szafarz M, et al (2021)

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating.

Pharmaceuticals (Basel, Switzerland), 14(3):.

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.

RevDate: 2021-05-28
CmpDate: 2021-05-28

Calder AN, Yu T, Dahir NS, et al (2021)

Ghrelin Receptors Enhance Fat Taste Responsiveness in Female Mice.

Nutrients, 13(4):.

Ghrelin is a major appetite-stimulating neuropeptide found in circulation. While its role in increasing food intake is well known, its role in affecting taste perception, if any, remains unclear. In this study, we investigated the role of the growth hormone secretagogue receptor's (GHS-R; a ghrelin receptor) activity in the peripheral taste system using feeding studies and conditioned taste aversion assays by comparing wild-type and GHS-R-knockout models. Using transgenic mice expressing enhanced green fluorescent protein (GFP), we demonstrated GHS-R expression in the taste system in relation phospholipase C ß2 isotype (PLCβ2; type II taste cell marker)- and glutamate decarboxylase type 67 (GAD67; type III taste cell marker)-expressing cells using immunohistochemistry. We observed high levels of co-localization between PLCβ2 and GHS-R within the taste system, while GHS-R rarely co-localized in GAD67-expressing cells. Additionally, following 6 weeks of 60% high-fat diet, female Ghsr-/- mice exhibited reduced responsiveness to linoleic acid (LA) compared to their wild-type (WT) counterparts, while no such differences were observed in male Ghsr-/- and WT mice. Overall, our results are consistent with the interpretation that ghrelin in the taste system is involved in the complex sensing and recognition of fat compounds. Ghrelin-GHS-R signaling may play a critical role in the recognition of fatty acids in female mice, and this differential regulation may contribute to their distinct ingestive behaviors.

RevDate: 2021-06-11

Wu CH, Ramos R, Katz DB, et al (2021)

Homeostatic synaptic scaling establishes the specificity of an associative memory.

Current biology : CB, 31(11):2274-2285.e5.

Correlation-based (Hebbian) forms of synaptic plasticity are crucial for the initial encoding of associative memories but likely insufficient to enable the stable storage of multiple specific memories within neural circuits. Theoretical studies have suggested that homeostatic synaptic normalization rules provide an essential countervailing force that can stabilize and expand memory storage capacity. Although such homeostatic mechanisms have been identified and studied for decades, experimental evidence that they play an important role in associative memory is lacking. Here, we show that synaptic scaling, a widely studied form of homeostatic synaptic plasticity that globally renormalizes synaptic strengths, is dispensable for initial associative memory formation but crucial for the establishment of memory specificity. We used conditioned taste aversion (CTA) learning, a form of associative learning that relies on Hebbian mechanisms within gustatory cortex (GC), to show that animals conditioned to avoid saccharin initially generalized this aversion to other novel tastants. Specificity of the aversion to saccharin emerged slowly over a time course of many hours and was associated with synaptic scaling down of excitatory synapses onto conditioning-active neuronal ensembles within gustatory cortex. Blocking synaptic scaling down in the gustatory cortex enhanced the persistence of synaptic strength increases induced by conditioning and prolonged the duration of memory generalization. Taken together, these findings demonstrate that synaptic scaling is crucial for sculpting the specificity of an associative memory and suggest that the relative strengths of Hebbian and homeostatic plasticity can modulate the balance between stable memory formation and memory generalization.

RevDate: 2021-05-12

Igarashi A, Ogasawara S, Takagi R, et al (2021)

Acute Oral Calcium Suppresses Food Intake Through Enhanced Peptide-YY Secretion Mediated by the Calcium-Sensing Receptor in Rats.

The Journal of nutrition, 151(5):1320-1328.

BACKGROUND: Dietary calcium has been proposed to reduce appetite in human studies. Postprandial satiety is mainly controlled by gut hormones. However, the effect of calcium on appetite and the role of gut hormones remain unclear.

OBJECTIVES: We examined whether oral administration of calcium reduces food intake in rats and investigated the underlying mechanism.

METHODS: Male Sprague Dawley rats (8-12 wk old) were used after an overnight fastifffng. In a series of 2 trials with 1-wk interval between challenges, food intake was measured 0.5-24 h after oral gavage of a vehicle (saline containing 1.5% carboxymethyl cellulose) as the control treatment, or the vehicle containing various calcium compounds [calcium chloride (CaCl2), calcium carbonate, calcium lactate, in a random order] at 150 mg calcium/kg dose. A conditional taste aversion test was conducted. In separate experiments, plasma calcium and gut hormone concentrations were measured 15 or 30 min after oral administration of the calcium compounds. In anesthetized rats, portal peptide-YY (PYY) concentrations were measured after intraluminal administration of a liquid meal with or without additional calcium.

RESULTS: Oral CaCl2 reduced food intake acutely (30 min, ∼20%, P < 0.05) compared with control rats, without taste aversion. Plasma PYY concentration was higher (100%, P < 0.05) in CaCl2-preloaded rats than in control rats, 15 min after administration. In anesthetized rats, luminal meal + CaCl2 induced a 4-fold higher increase in plasma PYY than the control treatment did. Oral administration of a calcium-sensing receptor (CaSR) agonist suppressed food intake (∼30%, P < 0.05), but CaCl2 and CaSR agonist did not suppress food intake under treatment with a PYY receptor antagonist. Furthermore, the CaSR antagonist attenuated the effect of CaCl2 on food intake.

CONCLUSIONS: CaCl2 suppresses food intake partly by increasing CaSR-mediated PYY secretion in rats. Our findings could at least partially explain the satiating effect of calcium.

RevDate: 2021-04-19

Karavasili C, Gkaragkounis A, DG Fatouros (2021)

Patent landscape of pediatric-friendly oral dosage forms and administration devices.

Expert opinion on therapeutic patents [Epub ahead of print].

INTRODUCTION: The current availability of dosage forms designed specifically for children is limited, constituting common practice the use of unlicensed or off-labeled medicines and extemporaneous preparations. Swallowing difficulties and taste aversion are the primary reasons for medicine rejection; therefore, enhancing palatability and ease of administration are the most common approaches adopted to overcome these issues.

AREAS COVERED: A search of patents was performed for pediatric dosage forms and devices. The review aims to provide an overview on new formulation approaches and technologies adopted to develop pediatric-friendly dosage forms and devices, as well as on the regulatory efforts aiming to support the pediatrics market.

EXPERT OPINION: Children deserve medicines of the same efficacy, quality and safety as adults. The present review highlights the momentum developed by pharmaceutical industries in the field of pediatrics, since more than 60 patents have been published in the last 5 years. An increasing interest, especially in mini-tablets, orodispersible, and chewable dosage forms, as well as on excipients and methods, to achieve sufficient taste-masking was identified, recognizing also the need for coordinated research networks and sustainable collaborations across the public and private sectors to provide better medicines for children.

RevDate: 2021-03-12

Sabatini PV, Frikke-Schmidt H, Arthurs J, et al (2021)

GFRAL-expressing neurons suppress food intake via aversive pathways.

Proceedings of the National Academy of Sciences of the United States of America, 118(8):.

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

RevDate: 2021-01-29

Dannenhoffer CA, Werner DF, Varlinskaya EI, et al (2021)

Adolescent intermittent ethanol exposure does not alter responsiveness to ifenprodil or expression of vesicular GABA and glutamate transporters.

Developmental psychobiology [Epub ahead of print].

Adolescent intermittent ethanol (AIE) exposure in the rat results in a retention of adolescent-like responsiveness to ethanol into adulthood characterized by enhanced sensitivity to socially facilitating and decreased sensitivity to socially suppressing and aversive effects. Similar pattern of responsiveness to social and aversive effects of the selective glutamate NMDA NR2B receptor antagonist ifenprodil is evident in adolescent rats, suggesting that AIE would also retain this pattern of ifenprodil sensitivity into adulthood. Social (Experiment 1) and aversive (measured via conditioned taste aversion; Experiment 2) effects of ifenprodil were assessed in adult male and female rats following AIE exposure. Sensitivity to the social and aversive effects of ifenprodil was not affected by AIE exposure. Experiment 3 assessed protein expression of vesicular transporters of GABA (vGAT) and glutamate (vGlut2) within the prelimbic cortex and nucleus accumbens in adolescents versus adults and in AIE adults versus controls. vGlut2 expression was higher in adolescents relative to adults within the PrL, but lower in the NAc. AIE adults did not retain these adolescent-typical ratios. These findings suggest that AIE is not associated with the retention of adolescent-typical sensitivity to NR2B receptor antagonism, along with no AIE-induced shift in vGlut2 to vGAT ratios.

RevDate: 2021-01-27

Indigo NL, Jolly CJ, Kelly E, et al (2021)

Effects of learning and adaptation on population viability.

Conservation biology : the journal of the Society for Conservation Biology [Epub ahead of print].

Cultural adaptation is one means by which conservationists may help populations adapt to threats. A learned behavior may protect an individual from a threat, and the behavior can be transmitted horizontally (within generations) and vertically (between generations), rapidly conferring population-level protection. Although possible in theory, it remains unclear whether such manipulations work in a conservation setting; what conditions are required for them to work; and how they might affect the evolutionary process. We examined models in which a population can adapt through both genetic and cultural mechanisms. Our work was motivated by the invasion of highly toxic cane toads (Rhinella marina) across northern Australia and the resultant declines of endangered northern quolls (Dasyurus hallucatus), which attack and are fatally poisoned by the toxic toads. We examined whether a novel management strategy in which wild quolls are trained to avoid toads can reduce extinction probability. We used a simulation model tailored to quoll life history. Within simulations, individuals were trained and a continuous evolving trait determined innate tendency to attack toads. We applied this model in a population viability setting. The strategy reduced extinction probability only when heritability of innate aversion was low (<20%) and when trained mothers trained >70% of their young to avoid toads. When these conditions were met, genetic adaptation was slower, but rapid cultural adaptation kept the population extant while genetic adaptation was completed. To gain insight into the evolutionary dynamics (in which we saw a transitory peak in cultural adaptation over time), we also developed a simple analytical model of evolutionary dynamics. This model showed that the strength of natural selection declined as the cultural transmission rate increased and that adaptation proceeded only when the rate of cultural transmission was below a critical value determined by the relative levels of protection conferred by genetic versus cultural mechanisms. Together, our models showed that cultural adaptation can play a powerful role in preventing extinction, but that rates of cultural transmission need to be high for this to occur.

RevDate: 2021-02-05

Itoh A, Komatsuzaki Y, Lukowiak K, et al (2021)

Epicatechin increases the persistence of long-term memory formed by conditioned taste aversion in Lymnaea.

The Journal of experimental biology, 224(Pt 3): pii:jeb.238055.

We examined the effects of epicatechin (Epi), a flavonoid abundant in green tea and cocoa, on long-term memory (LTM) formed following conditioned taste aversion (CTA) training in Lymnaeastagnalis In CTA training, the snails learnt to avoid a food that initially they liked (i.e. sucrose). Twenty-four hours after CTA training, 67% of the trained snails showed a significant decrease in the feeding behaviour elicited by sucrose. Placing snails in the Epi solution in CTA training did not alter the percentage of snails exhibiting LTM, but it significantly increased LTM persistence. We also examined changes following Epi exposure in spontaneous activity of the cerebral giant cells (CGCs) that modulate feeding behaviour and are necessary for CTA-LTM. Our data suggest that Epi causes a decrease in CGC activity and increases LTM persistence, possibly via a GABAergic mechanism.

RevDate: 2021-03-29
CmpDate: 2021-03-29

Toyoda H, Katagiri A, Kato T, et al (2020)

Intranasal Administration of Rotenone Reduces GABAergic Inhibition in the Mouse Insular Cortex Leading to Impairment of LTD and Conditioned Taste Aversion Memory.

International journal of molecular sciences, 22(1):.

The pesticide rotenone inhibits mitochondrial complex I and is thought to cause neurological disorders such as Parkinson's disease and cognitive disorders. However, little is known about the effects of rotenone on conditioned taste aversion memory. In the present study, we investigated whether intranasal administration of rotenone affects conditioned taste aversion memory in mice. We also examined how the intranasal administration of rotenone modulates synaptic transmission and plasticity in layer V pyramidal neurons of the mouse insular cortex that is critical for conditioned taste aversion memory. We found that the intranasal administration of rotenone impaired conditioned taste aversion memory to bitter taste. Regarding its cellular mechanisms, long-term depression (LTD) but not long-term potentiation (LTP) was impaired in rotenone-treated mice. Furthermore, spontaneous inhibitory synaptic currents and tonic GABA currents were decreased in layer V pyramidal neurons of rotenone-treated mice compared to the control mice. The impaired LTD observed in pyramidal neurons of rotenone-treated mice was restored by a GABAA receptor agonist muscimol. These results suggest that intranasal administration of rotenone decreases GABAergic synaptic transmission in layer V pyramidal neurons of the mouse insular cortex, the result of which leads to impairment of LTD and conditioned taste aversion memory.

RevDate: 2021-04-19
CmpDate: 2021-04-19

Kawabata F, Yoshida Y, Inoue Y, et al (2021)

Research Note: Behavioral preference and conditioned taste aversion to oleic acid solution in chickens.

Poultry science, 100(1):372-376.

A functional fatty acid taste receptor, GPR120, is present in chicken oral tissues, and chickens show a preference for lipid in feed. However, it remains unclear whether chickens can detect fatty acids. To address this issue, we adopted 2 behavioral paradigms: a one-bowl drinking test to evaluate the preference for oleic acid solution and a conditioned taste aversion test to investigate the role of gustation in chickens' ability to detect oleic acid. In the one-bowl drinking test, chickens did not show any preference for solution containing 0.001, 0.01, 0.03, 0.1, or 30 mmol/L oleic acid although 30 mmol/L oleic acid was enough to fully activate GPR120, confirmed by Ca2+ imaging. On the other hand, chickens conditioned to avoid 30 mmol/L oleic acid solution also learned to avoid the solution. These results suggested that chickens have a gustatory perception of oleic acid solution but do not have a preference for it. The present results support the idea that chickens prefer lipid in feed, not only by a postingestive effect but also by sensing the taste of fatty acid.

RevDate: 2021-02-25

Wyszogrodzka E, Dyr W, Siwińska-Ziółkowska A, et al (2021)

Higher sensitivity to ethanol's aversive properties in WLP (Warsaw Low Preferring) vs. WHP (Warsaw High Preferring) rats.

Alcohol (Fayetteville, N.Y.), 90:67-73.

Ethanol can have both an aversive and rewarding effect, which may have a significant relationship to its individual preference. So far, the reasons for the high and low ethanol preference in the WHP (Warsaw High Preferring) and WLP (Warsaw Low Preferring) lines have not been found. WHP rats spontaneously drink over 5 g/kg/day of ethanol, while WLP rats drink under 2 g/kg/day. The purpose of the work was to study the sensitivity of WHP and WLP rats to the aversive effects of ethanol at doses of 1.5 g/kg and 2.0 g/kg in the conditioned taste aversion (CTA) procedure. Lower doses (0.5 and 1.0 g/kg, i.p. [intraperitoneally]) were tested earlier and only 1.0 g/kg produced a slight aversion in WLP rats. The secondary aim was to check the additional potential factors (blood ethanol concentration, pain sensitivity, anxiety-related behavior, learning, and memory) that may constitute an important differentiating feature of the WHP and WLP lines. For this purpose, the following tests were conducted: blood ethanol concentration, novel object recognition (NOR), flinch-jump, hot-plate, and elevated plus maze (EPM). The 1.5 g/kg i.p. dose of ethanol caused the development of an aversion only in WLP rats and the aversion extinguished in the post-conditioning phase. The 2.0 g/kg i.p. dose of ethanol resulted in the development of an aversion in both the tested groups, with the aversion being maintained throughout the whole post-conditioning period only in the WLP rats. There were no differences between the lines in terms of the blood ethanol concentration and the EPM tests. WHP rats had a higher pain sensitivity compared to WLP rats in flinch-jump and hot-plate tests. WLP rats showed a shorter exploration time for both objects compared to WHP in the NOR test. In conclusion, WHP and WLP rats differ in sensitivity to the aversive effects of ethanol. This difference may partially explain their opposite ethanol preference.

RevDate: 2021-01-05

Robinson SL, Dornellas APS, Burnham NW, et al (2020)

Distinct and Overlapping Patterns of Acute Ethanol-Induced C-Fos Activation in Two Inbred Replicate Lines of Mice Selected for Drinking to High Blood Ethanol Concentrations.

Brain sciences, 10(12):.

The inbred high drinking in the dark (iHDID1 and iHDID2) strains are two replicate lines bred from the parent HS/Npt (HS) line for achieving binge levels of blood ethanol concentration (≥80 mg/dL BEC) in a four-hour period. In this work, we sought to evaluate differences in baseline and ethanol-induced c-Fos activation between the HS, iHDID1, and iHDID2 genetic lines in brain regions known to process the aversive properties of ethanol.

METHODS: Male and female HS, iHDID1, and iHDID2 mice underwent an IP saline 2 3 g/kg ethanol injection. Brain sections were then stained for c-Fos expression in the basolateral/central amygdala (BLA/CeA), bed nucleus of the stria terminals (BNST), A2, locus coeruleus (LC), parabrachial nucleus (PBN), lateral/medial habenula (LHb/MHb), paraventricular nucleus of the thalamus (PVT), periaqueductal gray (PAG), Edinger-Westphal nuclei (EW), and rostromedial tegmental nucleus (RMTg).

RESULTS: The iHDID1 and iHDID2 lines showed similar and distinct patterns of regional c-Fos; however, in no region did the two both significantly differ from the HS line together.

CONCLUSIONS: These data lend further support to altered baseline or ethanol-induced activation in brain regions associated with processing the aversive properties of ethanol in the iHDID1 and iHDID2 genetic lines.

RevDate: 2021-05-14
CmpDate: 2021-05-14

Stensmyr MC, SJC Caron (2020)

Neuroscience: The Secret of Sauce Béarnaise Syndrome Is in the Circuit.

Current biology : CB, 30(23):R1413-R1415.

During conditioned food aversion - a.k.a. sauce béarnaise syndrome - the ingestion of a spoiled food item leads to a lasting aversion towards cues reminiscent of the item. A new study finds that, in Drosophila, taste aversion depends on the immune system and the mushroom body.

RevDate: 2020-12-26

Nakai J, Totani Y, Hatakeyama D, et al (2020)

Another Example of Conditioned Taste Aversion: Case of Snails.

Biology, 9(12):.

Conditioned taste aversion (CTA) in mammals has several specific characteristics: (1) emergence of a negative symptom in subjects due to selective association with a taste-related stimulus, (2) robust long-term memory that is resistant to extinction induced by repeated presentation of the conditioned stimulus (CS), (3) a very-long-delay presentation of the unconditioned stimulus (US), and (4) single-trial learning. The pond snail, Lymnaea stagnalis, can also form a CTA. Although the negative symptoms, like nausea, in humans cannot be easily observed in invertebrate animal models of CTA, all the other characteristics of CTA seem to be present in snails. Selective associability was confirmed using a sweet sucrose solution and a bitter KCl solution. Once snails form a CTA, repeated presentation of the CS does not extinguish the CTA. A long interstimulus interval between the CS and US, like in trace conditioning, still results in the formation of a CTA in snails. Lastly, even single-trial learning has been demonstrated with a certain probability. In the present review, we compare, in detail, CTA in mammals and snails, and discuss the possible molecular events in CTA.

RevDate: 2021-04-14
CmpDate: 2021-04-14

Haley MS, Bruno S, Fontanini A, et al (2020)

LTD at amygdalocortical synapses as a novel mechanism for hedonic learning.

eLife, 9:.

A novel, pleasant taste stimulus becomes aversive if associated with gastric malaise, a form of learning known as conditioned taste aversion (CTA). CTA is common to vertebrates and invertebrates and is an important survival response: eating the wrong food may be deadly. CTA depends on the gustatory portion of the insular cortex (GC) and the basolateral nucleus of the amygdala (BLA) however, its synaptic underpinnings are unknown. Here we report that CTA was associated with decreased expression of immediate early genes in rat GC of both sexes, and with reduced amplitude of BLA-GC synaptic responses, pointing to long-term depression (LTD) as a mechanism for learning. Indeed, association of a novel tastant with induction of LTD at the BLA-GC input in vivo was sufficient to change the hedonic value of a taste stimulus. Our results demonstrate a direct role for amygdalocortical LTD in taste aversion learning.

RevDate: 2021-05-07
CmpDate: 2021-05-07

Morin JP, Rodríguez-Nava E, Torres-García VM, et al (2021)

Muscarinic receptor signaling in the amygdala is required for conditioned taste aversion.

Neuroscience letters, 740:135466.

The sense of taste provides information regarding the nutrient content, safety or potential toxicity of an edible. This is accomplished via a combination of innate and learned taste preferences. In conditioned taste aversion (CTA), rats learn to avoid ingesting a taste that has previously been paired with gastric malaise. Recent evidence points to a role of cholinergic muscarinic signaling in the amygdala for the learning and storage of emotional memories. The present study tested the participation of muscarinic receptors in the amygdala during the formation of CTA by infusing the non-specific antagonist scopolamine into the basolateral or central subnuclei before or after conditioning, as well as before retrieval. Our data show that regardless of the site of infusion, pre-conditioning administration of scopolamine impaired CTA acquisition whereas post-conditioning infusion did not affect its storage. Also, infusions into the basolateral but not in the central amygdala before retrieval test partially reduced the expression of CTA. Our results indicate that muscarinic receptors activity is required for acquisition but not consolidation of CTA. In addition, our data add to recent evidence pointing to a role of cholinergic signaling in peri-hippocampal structures in the process of memory retrieval.

RevDate: 2021-04-17

Steinfeld MR, ME Bouton (2021)

Renewal of goal direction with a context change after habit learning.

Behavioral neuroscience, 135(1):79-87.

An instrumental action can be goal-directed after a moderate amount of practice and then convert to habit after more extensive practice. Recent evidence suggests, however, that habits can return to action status after different environmental manipulations. The present experiments therefore asked whether habit learning interferes with goal direction in a context-dependent manner like other types of retroactive interference (e.g., extinction, punishment, counterconditioning). In Experiment 1, rats were given a moderate amount of instrumental training to form an action in one context (Context A) and then more extended training of the same response to form a habit in another context (Context B). We then performed reinforcer devaluation with taste aversion conditioning in both contexts, and tested the response in both contexts. The response remained habitual in Context B, but was goal-directed in Context A, indicating renewal of goal direction after habit learning. Experiment 2 expanded on Experiment 1 by testing the response in a third context (Context C). It found that the habitual response also renewed as action in this context. Together, the results establish a parallel between habit and extinction learning: Conversion to habit does not destroy action knowledge, but interferes with it in a context-specific way. They are also consistent with other results suggesting that habit is specific to the context in which it is learned, whereas goal-direction can transfer between contexts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

RevDate: 2021-01-30

Fonseca E, Sandoval-Herrera V, Simon SA, et al (2020)

Behavioral Disassociation of Perceived Sweet Taste Intensity and Hedonically Positive Palatability.

eNeuro, 7(5):.

The intensity of sucrose (its perceived concentration) and its palatability (positive hedonic valence associated with ingestion) are two taste attributes that increase its attractiveness and overconsumption. Although both sensory attributes covary, in that increases in sucrose concentration leads to similar increases in its palatability, this covariation does not imply that they are part of the same process or whether they represent separate processes. Both these possibilities are considered in the literature. For this reason, we tested whether sucrose's perceived intensity could be separated from its hedonically positive palatability. To address this issue, rats were trained in a sucrose intensity task to report the perceived intensity of a range of sucrose concentrations before and after its palatability was changed using a conditioned taste aversion (CTA) protocol. We found that the subjects' performance remained essentially unchanged, although its palatability was changed from hedonically positive to negative. Overall, these data demonstrate that sucrose's perceived intensity and its positive palatability can be dissociated, meaning that changes of one taste attribute render the other mostly unaffected. Thus, the intensity attribute is sufficient to inform the perceptual judgments of sucrose's concentrations.

RevDate: 2021-01-27
CmpDate: 2021-01-27

Sato T, Hirai Y, Su S, et al (2020)

Involvement of the area postrema and the nucleus tractus solitarius in the emetogenic action of emetine in rats.

Journal of oral biosciences, 62(4):310-314.

OBJECTIVES: The aim of the present study was to demonstrate the effective dose of emetine for inducing nausea and/or emesis, and the effects of emetine on the excitability of central neurons in the area postrema (AP) and the nucleus tractus solitarius (NTS).

METHODS: Rats were used as experimental animals. We measured the conditioned taste aversion (CTA) induced by the intraperitoneal administration of emetine solution (0.03, 0.1, 0.3, 0.5, and 1.0 mM in saline) and that of only saline. We also performed immunohistochemical analyses of c-Fos expression in the area postrema and the NTS, to examine changes in the excitability of brainstem neurons that may be responsible for emetine-induced nausea and/or emesis.

RESULTS: The emetine-induced CTA occurred in a dose-dependent manner. The half maximal inhibitory concentration (IC50) of emetine on the saccharin preference was calculated to be 0.348 mM using the Hill equation. In the animals injected with emetine (0.5 and 1.0 mM), many c-Fos-like immunoreactive (Fos-ir) cells were observed in the area postrema and the NTS, while few Fos-ir cells were identified in the animals injected with saline. The average number of Fos-ir cells in the area postrema and the NTS was significantly larger in animals injected with emetine than in animals injected with saline.

CONCLUSIONS: The present study demonstrated a dose-responsive manner of emetine effects and emetine-induced upregulation of neuronal excitability in the area postrema and the NTS that form a part of the induction mechanisms of emetine-induced nausea and/or emesis.

RevDate: 2021-01-26
CmpDate: 2021-01-26

Tobajas J, Ruiz-Aguilera MJ, López-Bao JV, et al (2020)

The effectiveness of conditioned aversion in wolves: Insights from experimental tests.

Behavioural processes, 181:104259.

It has been suggested that conditioned food aversion (CFA) could be a potential non-lethal intervention by which to deter attacks on livestock by large carnivores. CFA occurs when an animal associates the characteristics of a food with an illness, thus rejecting that food in subsequent encounters. CFA can be associated with an artificial odour during conditioning. Despite the debate surrounding the use of this intervention, more studies evaluating the effectiveness of CFA are necessary. We experimentally evaluated the potential of microgranulated levamisole + a vanilla odour cue to induce CFA in captive Iberian wolves (Canis lupus signatus). Four out of the five wolves treated showed an aversion to the meat for a minimum of one month after conditioning. The microgranulated presentation masked the flavour and smell of the levamisole but increased its volume, which may have facilitated its detection by the wolves. We also observed that the strength of the odour played an important role in the aversion extinction. The use of microgranulated levamisole + an odour cue has the potential to be used as an intervention by which to induce aversive conditioning in wolves in the wild, although rigorous field tests are required. We discuss the potential of CFA to deter attacks on livestock by large carnivores.

RevDate: 2021-04-21
CmpDate: 2021-02-01

Fukabori R, Iguchi Y, Kato S, et al (2020)

Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(43):8367-8385.

The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and β-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.

RevDate: 2021-04-05

Grijalva LE, Miranda MI, RG Paredes (2021)

Differential changes in GAP-43 or synaptophysin during appetitive and aversive taste memory formation.

Behavioural brain research, 397:112937.

Association between events in time and space is a major mechanism for all animals, including humans, which allows them to learn about the world and potentially change their behavior in the future to adapt to different environments. Conditioning taste aversion (CTA) is a single-trial learning paradigm where animals are trained to avoid a novel flavor which is associated with malaise. Many variables can be analyzed with this model and the circuits involved are well described. Thus, the amygdala and the gustatory cortex (GC) are some of the most relevant structures involved in CTA. In the present study we focused in plastic changes that occur during appetitive and/or aversive taste memory formation. Previous studies have demonstrated that memory consolidation, in hippocampal dependent paradigms, induces plastic changes like increase in the concentration of proteins considered as markers of neuronal plasticity, such as the growth associated protein 43 (GAP-43) and synaptophysin (SYN). In the present experiment in male rats we evaluated changes in GAP-43 and SYN expression, using immunofluorescence, induce by the formation of aversive and appetitive taste memory. We found that taste aversive memory formation can induce an increase in GAP-43 in the granular layer of the GC. Furthermore, we also found an increase in SYN expression in both layers of the GC, the basolateral amygdala (BLA) and the central amygdala (CeA). These results suggest that aversive memory representation induces a new circuitry (inferred from an increase in GAP 43). On the other hand, an appetitive taste learning increased SYN expression in the GC (both layers), the BLA and the CeA without any changes in GAP 43. Together these results indicate that aversive memory formation induces structural and synaptic changes, while appetitive memory formation induces synaptic changes; suggesting that aversive and appetitive memories require a different set of cortical and amygdala plastic changes.

RevDate: 2021-04-06
CmpDate: 2021-04-06

Heyes C, Chater N, DM Dwyer (2020)

Sinking In: The Peripheral Baldwinisation of Human Cognition.

Trends in cognitive sciences, 24(11):884-899.

The Baldwin effect is a hypothetical process in which a learned response to environmental change evolves a genetic basis. Modelling has shown that the Baldwin effect offers a plausible and elegant explanation for the emergence of complex behavioural traits, but there is little direct empirical evidence for its occurrence. We highlight experimental evidence of the Baldwin effect and argue that it acts preferentially on peripheral rather than on central cognitive processes. Careful scrutiny of research on taste-aversion and fear learning, language, and imitation indicates that their efficiency depends on adaptively specialised input and output processes: analogues of scanner and printer interfaces that feed information to core inference processes and structure their behavioural expression.

RevDate: 2020-11-04
CmpDate: 2020-11-04

Galistu A, PS D'Aquila (2020)

Memantine effects on ingestion microstructure and the effect of administration time: A within-subject study.

PloS one, 15(9):e0239270.

In a between-subject comparison of two memantine administration schedules we observed that treatment with the NMDA receptor antagonist memantine before testing sessions reduced ingestion of a 10% sucrose solution in rats, due to reduced licking burst size, thus suggesting a blunted hedonic response. Conversely, daily post-session administration reduced burst number, indicating a reduced level of behavioural activation, likely due to the development of conditioned taste aversion (CTA). In this study, the effect of pre-session and post-session memantine administration was investigated within-subjects. Memantine was administered in daily intraperitoneal injections for 13 days, on alternate days, either 1-h before-"before testing" sessions-or immediately after a 30-min session-"after testing" sessions. The effects on the microstructure of licking for a 10% sucrose solution were examined in the course of treatment and for 21 days after treatment discontinuation. The results show reduced burst size in the "before testing" sessions, without effects on the intra-burst lick rate, an index of motoric effects. Moreover, burst number was reduced since the third session of both administration conditions until the end of treatment. Interestingly, the effect of memantine of reducing the activation of ingestive behaviour was less pronounced in this study with respect to that observed with the previous study post-session administration schedule, in spite of the longer treatment. This apparent paradox might be explained if one considers these effects as instances of a memory-related effect, such as the development of CTA. In the framework of this hypothesis, the "before testing" sessions, not being followed by memantine administration, can be considered as extinction sessions performed every other day. Moreover, the animals treated with memantine at the highest dose failed to recover to pre-treatment ingestion levels 21 days after treatment discontinuation, while the animals treated after testing sessions in the previously published study showed a complete recovery well before the 15th day test. Within the same interpretative framework, this might depend by the reduced number and frequency of the extinction trials-i.e. the number of the sessions run after treatment discontinuation-in the present study. These results provide further support to the conclusion that memantine administration before sessions reduce burst size, an effect which is likely due to blockade of NMDA receptors occurring during behavioural testing. The observation that this effect can be obtained even in absence of a reduced intra-burst lick rate, which rules out the involvement of motor impairment, provides an important piece of evidence in support to the interpretation of this effect as a blunted hedonic response. Moreover, these results provide further evidence that burst number reduction is due to a memory-related effect induced by memantine administration after sessions.

RevDate: 2021-03-01
CmpDate: 2021-03-01

Arieli E, Gerbi R, Shein-Idelson M, et al (2020)

Temporally-precise basolateral amygdala activation is required for the formation of taste memories in gustatory cortex.

The Journal of physiology, 598(23):5505-5522.

KEY POINTS: The basolateral amygdala (BLA), the nucleus basalis magnocellularis (NBM), and the gustatory cortex (GC) are involved in taste processing, taste memory formation and conditioned taste aversion (CTA) learning, but their fine-temporal interactions that support these cognitive functions are not well understood. We found that the formation of novel-taste and CTA memories in the GC depend on a distinct late response (700-3000 ms) of BLA projection neurons. In contrast, BLA activity was not essential for palatability-related behaviour and coding in the GC prior to CTA. We identified the BLA→NBM pathway as a potential pathway for the transmission of taste novelty information, required for the formation of taste and CTA memories in the GC. Our results demonstrate how neuronal dynamics across multiple brain regions support long-term memory formation.

ABSTRACT: Learning to associate malaise with the intake of novel food is critical for survival. Since food poisoning may take hours to take effect, animals developed brain circuits to transform the current novel taste experience into a taste memory trace (TMT) and bridge this time lag. Ample studies showed that the basolateral amygdala (BLA), the nucleus basalis magnocellularis (NBM) and the gustatory cortex (GC) are involved in TMT formation and taste-malaise association. However, how dynamic activity across these brain regions during novel taste experience promotes the formation of these memories is currently unknown. We used the conditioned taste aversion (CTA) learning paradigm in combination with short-term optogenetics and electrophysiological recording in rats to test the hypothesis that temporally specific activation of BLA projection neurons is essential for TMT formation in the GC, and consequently CTA. We found that a short late epoch (LE, 700-3000 ms), but not the early epoch (EE, 0-500 ms), of BLA activation during novel taste experience is essential for normal CTA, for early c-Fos expression in the GC (a marker of TMT formation) and for the post-CTA changes in GC ensemble palatability coding. Interestingly, BLA activity was not required for intact taste identity or palatability perceptions before CTA. We further show that BLA-LE information is transmitted to GC through the BLA→NBM pathway where it affects the formation of taste memories. These results expose the dependence of long-term memory formation on specific temporal windows during sensory responses and the distributed circuits supporting this dependence.

RevDate: 2021-02-25
CmpDate: 2021-02-25

Levitan D, Liu C, Yang T, et al (2020)

Deletion of Stk11 and Fos in mouse BLA projection neurons alters intrinsic excitability and impairs formation of long-term aversive memory.

eLife, 9:.

Conditioned taste aversion (CTA) is a form of one-trial learning dependent on basolateral amygdala projection neurons (BLApn). Its underlying cellular and molecular mechanisms remain poorly understood. RNAseq from BLApn identified changes in multiple candidate learning-related transcripts including the expected immediate early gene Fos and Stk11, a master kinase of the AMP-related kinase pathway with important roles in growth, metabolism and development, but not previously implicated in learning. Deletion of Stk11 in BLApn blocked memory prior to training, but not following it and increased neuronal excitability. Conversely, BLApn had reduced excitability following CTA. BLApn knockout of a second learning-related gene, Fos, also increased excitability and impaired learning. Independently increasing BLApn excitability chemogenetically during CTA also impaired memory. STK11 and C-FOS activation were independent of one another. These data suggest key roles for Stk11 and Fos in CTA long-term memory formation, dependent at least partly through convergent action on BLApn intrinsic excitability.

RevDate: 2021-03-03
CmpDate: 2021-01-01

Hurley SW, RM Carelli (2020)

Activation of Infralimbic to Nucleus Accumbens Shell Pathway Suppresses Conditioned Aversion in Male But Not Female Rats.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(36):6888-6895.

Hedonic processing plays an integral role in directing appropriate behavior, but disrupted hedonic processing is associated with psychiatric disorders such as depression. The infralimbic cortex (IL) is a key structure in affective processing in rodents and activation of its human homolog, the ventromedial prefrontal cortex, has been implicated in suppressing aversive states. Here, we tested whether optogenetic activation of glutamatergic projections from the IL to the nucleus accumbens shell (NAcSh) suppresses the aversive impact of sucrose devalued using the conditioned taste aversion paradigm in males and female rats. In naive rats, no significant differences in appetitive or aversive taste reactivity (TR) to sucrose was observed indicating that initial sucrose palatability was equivalent across sex. However, we found that optical activation of the IL-NAcSh pathway during intraoral infusion of devalued sucrose inhibited aversive TR in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a two-bottle test both males and females with a history of IL-NAcSh stimulation exhibited greater preference for sucrose. Optical pathway activation failed to alter TR to innately bitter quinine in either sex. Finally, both sexes lever pressed to self-stimulate the IL-NAcSh pathway. These results indicate that the IL-NAcSh pathway plays an important role in suppressing learned aversive states selectively in males but spares hedonic processing of innately aversive tastants. Further, pathway activation is reinforcing in both sexes, indicating that suppression of conditioned aversive TR can be dissociable from the effects of unconditioned rewarding properties of IL-NAcSh pathway activation.SIGNIFICANCE STATEMENT Negative emotional states contribute to psychiatric disorders including depression and substance use disorders. In this study, we examined whether brain circuitry previously implicated in suppressing negative emotional states in humans can inhibit learned aversion in male and female rats. We found that optical activation of the infralimbic to nucleus accumbens shell pathway attenuates learned aversive responses in male but not female rats, indicating an important sex difference in the function of this brain pathway. Furthermore, we found that pathway stimulation was reinforcing in both sexes. Collectively, these findings support the role of the infralimbic cortex and its projection to the nucleus accumbens shell in suppressing learned negative emotional states and highlight an important sex-specific function of this pathway.

RevDate: 2020-11-06

Abe K, Kuroda M, Narumi Y, et al (2020)

Cortico-amygdala interaction determines the insular cortical neurons involved in taste memory retrieval.

Molecular brain, 13(1):107.

The insular cortex (IC) is the primary gustatory cortex, and it is a critical structure for encoding and retrieving the conditioned taste aversion (CTA) memory. In the CTA, consumption of an appetitive tastant is associated with aversive experience such as visceral malaise, which results in avoidance of consuming a learned tastant. Previously, we showed that levels of the cyclic-AMP-response-element-binding protein (CREB) determine the insular cortical neurons that proceed to encode a conditioned taste memory. In the amygdala and hippocampus, it is shown that CREB and neuronal activity regulate memory allocation and the neuronal mechanism that determines the specific neurons in a neural network that will store a given memory. However, cellular mechanism of memory allocation in the insular cortex is not fully understood. In the current study, we manipulated the neuronal activity in a subset of insular cortical and/or basolateral amygdala (BLA) neurons in mice, at the time of learning; for this purpose, we used an hM3Dq designer receptor exclusively activated by a designer drug system (DREADD). Subsequently, we examined whether the neuronal population whose activity is increased during learning, is reactivated by memory retrieval, using the expression of immediate early gene c-fos. When an hM3Dq receptor was activated only in a subset of IC neurons, c-fos expression following memory retrieval was not significantly observed in hM3Dq-positive neurons. Interestingly, the probability of c-fos expression in hM3Dq-positive IC neurons after retrieval was significantly increased when the IC and BLA were co-activated during conditioning. Our findings suggest that functional interactions between the IC and BLA regulates CTA memory allocation in the insular cortex, which shed light on understanding the mechanism of memory allocation regulated by interaction between relevant brain areas.

RevDate: 2021-02-17

Angulo R, Bustamante J, CA Arévalo-Romero (2020)

Age, sex and pre-exposure effects on acquisition and generalization of conditioned taste aversion in rats.

Behavioural brain research, 394:112813.

The main aim of the present study was to assess the effect of sex and aging in two pre-exposure learning effects, latent inhibition (LI) and perceptual learning (PL), with a conditioned taste aversion paradigm. Young adult (90 days) and aged (more than 18 months) males and females received 8 pre-exposure trials either with stimulus AX (LI conditions) or BX (PL conditions). Then, all animals received a conditioning trial with AX and two test trials, one with AX and other with BX. The level of generalization between AX and BX was assessed by means of the absolute level of consumption of BX and by the difference in consumption between both stimuli. The results showed an attenuation of latent inhibition as well a stronger generalization of conditioned taste aversion in females when generalization is inferred from the BX consumption. A facilitation of conditioning for the aged animals was also found regardless of the pre-exposed stimulus. Pre-exposures to BX resulted in little generalization, but pre-exposures to AX resulted in a very similar consumption of both compounds, indicating a strong generalization between them. Overall, the study provided novel evidence about the effect of sex and aging on taste aversion, raising at the same time some relevant questions about perceptual learning and how such pre-exposure effect has been typically assessed.

RevDate: 2021-01-26
CmpDate: 2021-01-26

Miranda MI, Rangel-Hernández A, Vera-Rivera G, et al (2021)

Taste association capabilities differ in high- and low-yawning rats versus outbred Sprague-Dawley rats after prolonged sugar consumption.

Animal cognition, 24(1):41-52.

Yawning is a stereotypical behavior pattern commonly associated with other behaviors such as grooming, sleepiness, and arousal. Several differences in behavioral and neurochemical characteristics have been described in high-yawning (HY) and low-yawning (LY) sublines from Sprague-Dawley (SD) rats that support they had changes in the neural mechanism between sublines. Differences in behavior and neurochemistry observed in yawning sublines could also overlap in processes needed during taste learning, particularly during conditioned taste aversion (CTA) and its latent inhibition. Therefore, the aim of this study was to analyze taste memory differences, after familiarization to novel or highly sweet stimuli, between yawning sublines and compare them with outbred SD rats. First, we evaluated changes in appetitive response during long-term sugar consumption for 14 days. Then, we evaluated the latent inhibition of CTA strength induced by this long pre-exposure, and we also measured aversive memory extinction rate. The results showed that SD rats and the two sublines developed similar CTA for novel sugar and significantly stronger appetitive memory after long-term sugar exposure. However, after 14 days of sugar exposure, HY and LY sublines were unable to develop latent inhibition of CTA after two acquisition trials and had a slower aversive memory extinction rate than outbreed rats. Thus, the inability of the HY and LY sublines to develop latent inhibition of CTA after long-term sugar exposure could be related to the time/context processes involved in long-term appetitive re-learning, and in the strong inbreeding that characterizes the behavioral traits of these sublines, suggesting that inbreeding affects associative learning, particularly after long-term exposure to sweet stimuli which reflects high familiarization.

RevDate: 2020-09-28

Angulo R, Bustamante J, Estades V, et al (2020)

Sex Differences in Cue Competition Effects With a Conditioned Taste Aversion Preparation.

Frontiers in behavioral neuroscience, 14:107.

This study aimed to test whether male and female rats might show differences in cue competition effects in a conditioned taste aversion (CTA) model. Experiment 1 tested for sex differences in overshadowing. After conditioning of a flavored compound AB or only one simple flavor A (being A and B a solution of sugar 10% and salt 1%, counterbalanced), consumption of the A solution at test was larger in the former than in the latter case only in males. Thus, the usual effect of overshadowing was observed in males but not in females. Experiment 2 examined sex differences in blocking with the same stimuli used in Experiment 1. After conditioning of AB, the consumption of B was larger for the animals that previously received a single conditioning trial with A than for those that received unpaired presentations of A and the illness. As observed in Experiment 1, the typical blocking effect appeared only in males but not in females. The present findings thus support the hypothesis that sex dimorphism might be expressed in classical conditioning, or at least, in cue competition effects such as overshadowing and blocking with a taste aversion model.

RevDate: 2020-09-25

Lai Y, Despouy E, Sandoz JC, et al (2020)

Degradation of an appetitive olfactory memory via devaluation of sugar reward is mediated by 5-HT signaling in the honey bee.

Neurobiology of learning and memory, 173:107278.

Conditioned taste aversion (CTA) learning induces the devaluation of a preferred food through its pairing with a stimulus inducing internal illness. In invertebrates, it is still unclear how this aversive learning impairs the memories of stimuli that had been associated with the appetitive food prior to its devaluation. Here we studied this phenomenon in the honey bee and characterized its neural underpinnings. We first trained bees to associate an odorant (conditioned stimulus, CS) with appetitive fructose solution (unconditioned stimulus, US) using a Pavlovian olfactory conditioning. We then subjected the bees that learned the association to a CTA training during which the antennal taste of fructose solution was contingent or not to the ingestion of quinine solution, which induces malaise a few hours after ingestion. Only the group experiencing contingent fructose stimulation and quinine-based malaise exhibited a decrease in responses to the fructose and a concomitant decrease in odor-specific retention in tests performed 23 h after the original odor conditioning. Furthermore, injection of dopamine- and serotonin-receptor antagonists after CTA learning revealed that this long-term decrease was mediated by serotonergic signaling as its blockade rescued both the responses to fructose and the odor-specific memory 23 h after conditioning. The impairment of a prior CS memory by subsequent CTA conditioning confirms that bees retrieve a devaluated US representation when presented with the CS. Our findings further highlight the importance of serotonergic signaling in aversive learning in the bee and uncover mechanisms underlying aversive memories induced by internal illness in invertebrates.

RevDate: 2021-02-24
CmpDate: 2021-02-24

Molero-Chamizo A, GN Rivera-Urbina (2020)

Taste Processing: Insights from Animal Models.

Molecules (Basel, Switzerland), 25(14):.

Taste processing is an adaptive mechanism involving complex physiological, motivational and cognitive processes. Animal models have provided relevant data about the neuroanatomical and neurobiological components of taste processing. From these models, two important domains of taste responses are described in this review. The first part focuses on the neuroanatomical and neurophysiological bases of olfactory and taste processing. The second part describes the biological and behavioral characteristics of taste learning, with an emphasis on conditioned taste aversion as a key process for the survival and health of many species, including humans.

RevDate: 2021-03-25

Blednov YA, Da Costa A, Mayfield J, et al (2021)

Deletion of Tlr3 reduces acute tolerance to alcohol and alcohol consumption in the intermittent access procedure in male mice.

Addiction biology, 26(2):e12932.

Pharmacological studies implicate toll-like receptor 3 (TLR3) signaling in alcohol drinking. We examined the role of TLR3 in behavioral responses to alcohol and GABAergic drugs by studying Tlr3 -/- mice. Because of opposing signaling between TLR3 and MyD88 pathways, we also evaluated Myd88 -/- mice. Ethanol consumption and preference decreased in male but not in female Tlr3 -/- mice during two-bottle choice every-other-day (2BC-EOD) drinking. There were no genotype differences in either sex during continuous or limited-access drinking. Null mutations in Tlr3 or Myd88 did not alter conditioned taste aversion to alcohol and had small or no effects on conditioned place preference. The Tlr3 null mutation did not alter acute alcohol withdrawal. Male, but not female, Tlr3 -/- mice took longer than wild-type littermates to recover from ataxia by ethanol or diazepam and longer to recover from sedative-hypnotic effects of ethanol or gaboxadol, indicating regulation of GABAergic signaling by TLR3. Acute functional tolerance (AFT) to alcohol-induced ataxia was decreased in Tlr3 -/- mice but was increased in Myd88 -/- mice. Thus, MyD88 and TLR3 pathways coordinately regulate alcohol consumption and tolerance to intoxicating doses of alcohol and GABAergic drugs. Despite similar alcohol metabolism and similar amounts of total alcohol consumed during 2BC and 2BC-EOD procedures in C57BL/6J mice, only 2BC-EOD drinking induced tolerance to alcohol-induced ataxia. Ataxia recovery was inversely correlated with level of drinking in wild-type and Tlr3 -/- littermates. Thus, deleting Tlr3 reduces alcohol consumption by reducing AFT to alcohol and not by altering tolerance induced by 2BC-EOD drinking.

RevDate: 2021-01-27
CmpDate: 2021-01-27

Yamamura T, Nakamura F, Yasuo T, et al (2020)

Effect of the duration of a conditioned stimulus on component recognition in binary taste mixtures in rats.

Journal of oral biosciences, 62(3):267-271.

OBJECTIVES: The aim of this behavioral study was to investigate the duration of a conditioned stimulus (CS-duration) necessary for rats to recognize the components of a binary taste mixture in a conditioned taste aversion (CTA) paradigm as well as the relationship between CS-duration and their spontaneous recovery.

METHODS: The experimental rats were categorized under conditioned and control groups and further divided into three groups according to the CS-duration: 10, 30, and 60 s. As the test stimuli, a mixture of 100 mM sucrose (S) + 30 μM quinine hydrochloride (Q) and its components were used.

RESULTS: On day 1 of the CTA test, the number of licks (NL) for S + Q and S in all conditioned groups was significantly lower than that of the control group presented with CS for 60 s (CON-60), which was the representative control group determined by the initial CTA test. For Q, there was no significant difference between NL of the CTA group presented with CS for 10 s and that of CON-60; however, NL in the other two CTA groups, i.e., CTA-30 and CTA-60, was significantly lower than that of CON-60. When the rats were presented with a shorter CS-duration, they showed spontaneous recovery earlier depending on the CS-duration.

CONCLUSIONS: These results suggest that rats can recognize a binary taste mixture and its components using a CS-duration of more than 30 s and that spontaneous recovery from CTA learning depends on the CS- duration.

RevDate: 2021-06-07
CmpDate: 2021-06-07

Molero-Chamizo A, GN Rivera-Urbina (2020)

Temporal specificity of latent inhibition in rats with daily water restriction prior to taste conditioning.

Acta neurobiologiae experimentalis, 80(2):99-107.

Temporal specificity of latent inhibition of conditioned taste aversion (CTA) has been demonstrated after prolonged habituation to temporal contexts in the stages preceding conditioning, and it has been eliminated by restricting consumption during conditioning. However, it is not known if latent inhibition of CTA is still dependent on the temporal context when fluid consumption is limited in the stages prior to conditioning. We tested temporal specificity of latent inhibition in rats with (different time of day for the conditioning stage) and without (same time of day for pre-exposure and conditioning stages) temporal changes on the conditioning day. All animals had limited access to water in the morning sessions of the stages prior to the conditioning day and 15 min of free access to fluid in the evening sessions of these stages. Compared to animals without temporal changes between stages, animals with a different temporal context during conditioning did not show evidence of latent inhibition. Unlike the effects observed after taste stimulus restrictions during conditioning, these results suggest that the temporal specificity of latent inhibition of CTA is not abolished when access to water is limited in the stages preceding conditioning.

RevDate: 2021-04-27
CmpDate: 2021-04-27

Hao L, Kshatriya D, Li X, et al (2020)

Acute feeding suppression and toxicity of raspberry ketone [4-(4-hydroxyphenyl)-2-butanone] in mice.

Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association, 143:111512.

Raspberry ketone (RK; [4-(4-hydroxyphenyl)-2-butanone]) is used by the food and cosmetic industry as a flavoring agent. RK is also marketed as a dietary supplement for weight maintenance and appetite control. The purpose of the study was to characterize the acute feeding suppression with RK (64-640 mg/kg) by oral gavage in male and female C57BL/6J mice. Cumulative 24 h food intake was reduced at 200 mg/kg (24% feeding suppression) in males and reliably reduced at 640 mg/kg (49-77% feeding suppression). Feeding suppression was not associated with pica behavior over the range of doses or conditioned taste aversion. In a separate experiment, a single oral gavage of RK (640 mg/kg) resulted in approximate 43% mortality rate (6 out 14 male mice) within 2 days. Atrophy of white adipose tissue, splenic abnormalities, and thymus involution were noted after 2-4 days after oral gavage RK. Total white blood cell count, lymphocytes, monocytes, eosinophils were significantly lower, while mean red blood cells, hemoglobin, and hematocrit were significantly higher with RK treatment. Our findings indicated a dose-dependent feeding suppression with acute RK, but doses that reliable suppress food intake are associated with pathological changes.

RevDate: 2021-01-10

Csikós V, Varró P, Bódi V, et al (2020)

The mycotoxin deoxynivalenol activates GABAergic neurons in the reward system and inhibits feeding and maternal behaviours.

Archives of toxicology, 94(9):3297-3313.

Deoxynivalenol (DON) or vomitoxin, is a trichothecene mycotoxin produced mainly by Fusarium graminearum and culmorum. Mycotoxins or secondary metabolic products of mold fungi are micro-pollutants, which may affect human and animal health. The neuronal and behavioural actions of DON were analysed in the present study. To address, which neurons can be affected by DON, the neuronal activation pattern following intraperitoneal injection of DON (1 mg/kg) was investigated in adult male rats and the results were confirmed in mice, too. DON-induced neuronal activation was assessed by c-Fos immunohistochemistry. DON injection resulted in profound c-Fos activation in only the elements of the reward system, such as the accumbens nucleus, the medial prefrontal cortex, and the ventral tegmental area. Further double labelling studies suggested that GABAergic neurons were activated by DON treatment. To study the behavioural relevance of this activation, we examined the effect of DON on feed intake as an example of reward-driven behaviours. Following DON injection, feed consumption was markedly reduced but returned to normal the following day suggesting an inhibitory action of DON on feed intake without forming taste-aversion. To further test how general the effect of DON on goal-directed behaviours is, its actions on maternal behaviour was also examined. Pup retrieval latencies were markedly increased by DON administration, and DON-treated mother rats spent less time with nursing suggesting reduced maternal motivation. In a supplementary control experiment, DON did not induce conditioned place preference arguing against its addictive or aversive actions. The results imply that acute uptake of the mycotoxin DON can influence the reward circuit of the brain and exert inhibitory actions on goal-directed, reward-driven behaviours. In addition, the results also suggest that DON exposure of mothers may have specific implications.

RevDate: 2020-08-31

Huang ACW, Yu YH, He ABH, et al (2020)

Interactions between prelimbic cortex and basolateral amygdala contribute to morphine-induced conditioned taste aversion in conditioning and extinction.

Neurobiology of learning and memory, 172:107248.

The consequences of exciting or destroying the prelimbic cortex (PrL) or the basolateral amygdala (BLA) remain unclear, including the effects on morphine-induced conditioned taste aversion (CTA) in the conditioning and extinction phases, plasma corticosterone (CORT) levels, and c-Fos/p-ERK expressions in the subareas of the medial prefrontal cortex (i.e., PrL, infralimbic cortex [IL], cingulate cortex 1 [Cg1]), basolateral amygdala (BLA), central amygdala (CeA), hippocampus (i.e., CA1, CA2, CA3, and dentate gyrus [DG]), nucleus accumbens (NAc), lateral hypothalamus (LH), and piriform cortex (PC). During conditioning, excitation of the PrL glutamate neurons via NMDA injections disrupted morphine-induced CTA and decreased plasma CORT levels; moreover, c-Fos and p-ERK expression was hyperactive in the PrL and IL but hypoactive in the Cg1 and BLA. In conditioning, excitation of the BLA glutamate neurons via NMDA injections facilitated morphine-induced CTA and increased plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. During extinction, lesion of the PrL glutamate neurons via NMDA injections impaired morphine-induced CTA extinction and enhanced plasma CORT levels. The expression of c-Fos and p-ERK was hypoactive in the PrL and IL but hyperactive in the BLA. In extinction, excitation of the PrL glutamatergic neurons via NMDA injections facilitated morphine-induced CTA extinction and did not affect plasma CORT levels; moreover, the expression of c-Fos and p-ERK was hypoactive in the Cg1, PrL, and IL but hyperactive in the BLA. Altogether, the interaction between the PrL and BLA plays a balancing role in morphine-induced CTA conditioning and extinction. During conditioning, the activity of the PrL correlated negatively with plasma CORT secretions, whereas the activity of the BLA correlated positively with the plasma CORT levels. During extinction, the activity of the PrL correlated negatively with plasma CORT secretions; however, the activity of the BLA may be negatively associated with the plasma CORT levels. The data presented here provide some implications for morphine addiction and dependence.

RevDate: 2020-09-10

Nakai J, Totani Y, Kojima S, et al (2020)

Features of behavioral changes underlying conditioned taste aversion in the pond snail Lymnaea stagnalis.

Invertebrate neuroscience : IN, 20(2):8 pii:10.1007/s10158-020-00241-7.

Conditioned taste aversion (CTA) in the freshwater pulmonate Lymnaea stagnalis can be formed by presenting ten pairings of sucrose as the conditioned stimulus (CS) and KCl as the unconditioned stimulus (US). The CTA is consolidated to long-term memory (LTM) lasting longer than a month. In the present study, we examined the time course of protein synthesis-dependent period during the consolidation of Lymnaea CTA to LTM by pharmacological inhibition of transcription or translation. The robustness for CTA-LTM was then examined by extinction trials, i.e., repeated presentations of the CS alone. Furthermore, we evaluated the effects of the interstimulus interval (ISI) between the presentation of the CS and US. Our findings indicated that the protein synthesis-dependent period coincides with the CTA training. Repeated presentations of the CS alone after establishment of CTA did not extinguish the CTA, demonstrating the robustness of the CTA-LTM. The ISI ranged from 10 s to a few minutes, and there was no inverted U-shaped function between the ISI and the conditioned response (i.e., suppression of feeding). Thus, CTA still formed even when the presentation of the US was delayed. These features of Lymnaea CTA complement the knowledge for mammalian CTA.

RevDate: 2021-01-16

Steinfeld MR, ME Bouton (2020)

Context and renewal of habits and goal-directed actions after extinction.

Journal of experimental psychology. Animal learning and cognition, 46(4):408-421.

Instrumental behaviors that are goal-directed actions after moderate amounts of training can become habits after more extended training. Little research has asked how actions and habits are affected by retroactive interference treatments like extinction. The present experiments begin to fill this gap in the literature. In Experiments 1a and 1b, lever pressing in rats was minimally trained (1a) or extensively trained (1b) in one context (Context A), extinguished in a second context (Context B), and then tested in the acquisition context (Context A). Exposure to both contexts was equated and controlled throughout, and the status of the behavior as action or habit was determined by reinforcer devaluation methods (taste aversion conditioning). Results confirmed that action (1a) and habit (1b) renewed with action or habit status, respectively, when they were returned to Context A. Experiments 2a and 2b then similarly tested action and habit after extinction in an ABC renewal paradigm. Here, lever pressing that was trained in Context A and extinguished in Context B renewed as action in Context C regardless of whether it had been an action or habit before extinction. The apparent conversion of habit to action during renewal testing in Context C was consistent with other results suggesting that habits converted to action when the context was changed at the start of extinction. Together, the results suggest that extinction in a second context inhibits instrumental behaviors trained as either actions or habits in a context-specific manner. They also expand on prior findings suggesting that actions transfer across contexts, and that habits do not. A change of context may be sufficient to convert a habit to goal-directed action. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-09-28

Keating AV, Soto J, Forbes C, et al (2020)

Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms.

Pharmaceutics, 12(4):.

The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two in vivo (a human taste panel and a rat brief-access taste aversion (BATA) model) and one in vitro (sensor) method. The response of the Insent TS-5000Z electronic tongue was compared to the in vivo drug concentration found to elicit and suppress half the maximum taste response (EC50 in human and IC50 in rats). Using dose-relevant concentrations, an overarching rank order of bitterness was derived (rifampicin > ethambutol > pyrazinamid~isoniazid). In vitro, only ethambutol exhibited a linear response for all sensors/concentrations. Based on the EC50/IC50 generated, a 'taste index' was proposed to allow for anticipation of the likelihood of taste issues in practice, taking in account the saturability in the saliva and therapeutic doses; ethambutol and isoniazid were found to be the worst tasting using this measure. The study presents the first quantitative taste analysis of these life-saving drugs and has allowed for a comparison of three methods of obtaining such data. Such information allows the operator to identify and prioritise the drugs requiring taste masking to produce palatable formulations.

RevDate: 2021-01-21
CmpDate: 2021-01-21

Sandoval-Sánchez AR, Cedillo Zavaleta LN, Jiménez JC, et al (2020)

Administration of low doses of the 5-HT1A receptor agonist 8-OH-DPAT attenuates the discriminative signal of amphetamine in the conditioned taste aversion procedure.

Pharmacology, biochemistry, and behavior, 193:172932.

Several studies have reported that low doses of the 5-HT1A receptor agonist 8-OH-DPAT reduce cocaine-induced locomotor activity. However, it has also been reported that high doses of 8-OH-DPAT do not substitute for or alter the discriminative signal of cocaine (COC) or amphetamine (AMPH). This study aimed to evaluate the effects of low and high doses of the 5-HT1A agonist 8-OH-DPAT on the discriminative signal of AMPH using conditioned taste aversion as a drug discrimination procedure. Additionally, to establish a correlation between the behavioral effects in drug discrimination and changes in dopamine (DA) and gamma-aminobutyric acid (GABA) concentrations, we evaluated the effect of systemic administration of low or high doses of the 5-HT1A receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100135 on DA and GABA extracellular concentrations in the nucleus accumbens (nAcc) and ventral tegmental area (VTA), respectively, using cerebral microdialysis. The behavioral results showed that low but not high doses of 8-OH-DPAT produced a reduction in the AMPH-induced discriminative signal, while WAY100135 administration prevented such effects. The microdialysis results showed that a low dose of 8-OH-DPAT decreased extracellular DA concentrations in the nAcc and increased GABA concentrations in the VTA. Pretreatment with WAY100135 prevented these effects. These data support the hypothesis that 5-HT1A receptors modulate the behavioral effects of psychostimulant drugs, such as AMPH, through somatodendritic 5-HT1A autoreceptors in the raphe nucleus indicating that 5-HT1A receptors may be an important target for the development of pharmacological treatments for psychostimulant addiction.

RevDate: 2021-05-24
CmpDate: 2021-05-24

Nakajima S (2020)

Effect of pretrial running on running-based taste aversion learning in rats.

Journal of experimental psychology. Animal learning and cognition, 46(3):273-285.

Voluntary wheel running works as an effective unconditioned stimulus (US) to establish conditioned taste aversion (CTA) in rats with a preceding taste solution as a conditioned stimulus (CS): repeated CS-US pairings evoke avoidance of the CS in the two-choice (CS vs. tap water) test administered at the end of the training. Experiment 1 demonstrated that exposure to running immediately before each CS-US trial alleviates CTA. Subsequent two experiments explored the characteristics of the proximal US-preexposure effect: the alleviation of CTA by the pretrial running was not affected by changing the background contexts between the pretrial and the trial running (Experiment 2) or by signaling the pretrial running via another taste cue (Experiment 3). These results indicate the robustness of the proximal US-preexposure effect and fit well with the predictions of Wagner's (1976, 1978) priming theory. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-09-22

Totani Y, Nakai J, Dyakonova VE, et al (2020)

Induction of LTM following an Insulin Injection.

eNeuro, 7(2):.

The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). One-day food-deprived snails (day 1 snails) show the best CTA learning and memory, whereas more severely food-deprived snails (5 d) do not express good memory. However, previous studies showed that CTA-LTM was indeed formed in 5-d food-deprived snails (day 5 snails), but its recall was prevented by the effects of food deprivation. CTA-LTM recall in day 5 snails was expressed following 7 d of feeding and then 1 d of food deprivation (day 13 snails). In the present study, we thus hypothesized that memory recall occurs because day 13 snails are in an optimal internal state. One day of food deprivation before the memory test in day 13 snails increased the mRNA level of molluscan insulin-related peptide (MIP) in the CNS. Thus, we further hypothesized that an injection of insulin into day 5 snails following seven additional days with access to food (day 12 snails) activates CTA neurons and mimics the food deprivation state before the memory test in day 13 snails. Day 12 snails injected with insulin could recall the memory. In addition, the simultaneous injection of an anti-insulin receptor antibody and insulin into day 12 snails did not allow memory recall. Insulin injection also decreased the hemolymph glucose concentration. Together, the results suggest that an optimal internal state (i.e., a spike in insulin release and specific glucose levels) are necessary for LTM recall following CTA training in snails.

RevDate: 2021-04-02

Amaya KA, Stott JJ, KS Smith (2020)

Sign-tracking behavior is sensitive to outcome devaluation in a devaluation context-dependent manner: implications for analyzing habitual behavior.

Learning & memory (Cold Spring Harbor, N.Y.), 27(4):136-149.

Motivationally attractive cues can draw in behavior in a phenomenon termed incentive salience. Incentive cue attraction is an important model for animal models of drug seeking and relapse. One question of interest is the extent to which the pursuit of motivationally attractive cues is related to the value of the paired outcome or can become unrelated and habitual. We studied this question using a sign-tracking (ST) paradigm in rats, in which a lever stimulus preceding food reward comes to elicit conditioned lever-interaction behavior. We asked whether reinforcer devaluation by means of conditioned taste aversion, a classic test of habitual behavior, can modify ST to incentive cues, and whether this depends upon the manner in which reinforcer devaluation takes place. In contrast to several recent reports, we conclude that ST is indeed sensitive to reinforcer devaluation. However, this effect depends critically upon the congruence between the context in which taste aversion is learned and the context in which it is tested. When the taste aversion successfully transfers to the testing context, outcome value strongly influences ST behavior, both when the outcome is withheld (in extinction) and when animals can learn from outcome feedback (reacquisition). When taste aversion does not transfer to the testing context, ST remains high. In total, the extent to which ST persists after outcome devaluation is closely related to the extent to which that outcome is truly devalued in the task context. We believe this effect of context on devaluation can reconcile contradictory findings about the flexibility/inflexibility of ST. We discuss this literature and relate our findings to the study of habits generally.

RevDate: 2020-09-08
CmpDate: 2020-09-08

Xu LH, Yang Y, Liu HX, et al (2020)

Inner Ear Arginine Vasopressin-Vasopressin Receptor 2-Aquaporin 2 Signaling Pathway Is Involved in the Induction of Motion Sickness.

The Journal of pharmacology and experimental therapeutics, 373(2):248-260.

It has been identified that arginine vasopressin (AVP), vasopressin receptor 2(V2R), and the aquaporin 2 (AQP2) signaling pathway in the inner ear play important roles in hearing and balance functions through regulating the endolymph equilibrium; however, the contributions of this signaling pathway to the development of motion sickness are unclear. The present study was designed to investigate whether the activation of the AVP-V2R-AQP2 signaling pathway in the inner ear is involved in the induction of motion sickness and whether mozavaptan, a V2R antagonist, could reduce motion sickness. We found that both rotatory stimulus and intraperitoneal AVP injection induced conditioned taste aversion (a confirmed behavioral index for motion sickness) in rats and activated the AVP-V2R-AQP2 signaling pathway with a responsive V2R downregulation in the inner ears, and AVP perfusion in cultured epithelial cells from rat endolymphatic sacs induced similar changes in this pathway signaling. Vestibular training, V2R antagonist mozavaptan, or PKA inhibitor H89 blunted these changes in the V2R-AQP2 pathway signaling while reducing rotatory stimulus- or DDAVP (a V2R agonist)-induced motion sickness in rats and dogs. Therefore, our results suggest that activation of the inner ear AVP-V2R-AQP2 signaling pathway is potentially involved in the development of motion sickness; thus, mozavaptan targeting AVP V2Rs in the inner ear may provide us with a new application option to reduce motion sickness. SIGNIFICANCE STATEMENT: Motion sickness affects many people traveling or working. In the present study our results showed that activation of the inner ear arginine vasopressin-vaspopressin receptor 2 (V2R)-aquaporin 2 signaling pathway was potentially involved in the development of motion sickness and that blocking V2R with mozavaptan, a V2R antagonist, was much more effective in reducing motion sickness in both rat and dog; therefore, we demonstrated a new mechanism to underlie motion sickness and a new candidate drug to reduce motion sickness.

RevDate: 2021-05-25
CmpDate: 2021-05-25

László BR, Hormay E, Szabó I, et al (2020)

Disturbance of taste reactivity and other behavioral alterations after bilateral interleukin-1β microinjection into the cingulate cortex of the rat.

Behavioural brain research, 383:112537.

The anterior cingulate cortex (ACC), is known to be intimately involved in food-related motivational processes and their behavioral organization, primarily by evaluating hedonic properties of the relevant stimuli. In the present study, the involvement of cingulate cortical interleukin-1β (IL-1β) mediated mechanisms in a) gustation associated facial and somato-motor behavioral patterns of Wistar rats were examined in taste reactivity test (TR). In addition, b) conditioned taste aversion (CTA) paradigm was performed to investigate the role of these cytokine mechanisms in taste sensation associated learning processes, c) the general locomotor activity of the animals was observed in open field test (OPF), and d) the potentially negative reinforcing effect of IL-1β was examined in conditioned place preference test (CPP). During the TR test, species specific behavioral patterns in response to the five basic tastes were analyzed. Response rates of ingestive and aversive patterns of the cytokine treated and the control groups differed significantly in case of the weaker bitter (QHCl, 0.03 mM), and the stronger umami (MSG, 0.5 M) tastes. IL-1β itself did not elicit CTA, it did not interfere with the acquisition of LiCl induced CTA, and it also failed to cause place preference or aversion in the CPP test. In the OPF paradigm, however, significant differences were found between the cytokine treated and the control groups in the rearing and grooming, the number of crossings, and in the distance moved. Our results indicate the involvement of cingulate cortical IL-1β mechanisms in the control of taste perception and other relevant behavioral processes.

RevDate: 2020-12-13
CmpDate: 2020-03-31

Chia J, K Scott (2020)

Activation of specific mushroom body output neurons inhibits proboscis extension and sucrose consumption.

PloS one, 15(1):e0223034.

The ability to modify behavior based on prior experience is essential to an animal's survival. For example, animals may become attracted to a previously neutral odor or reject a previously appetitive food source based on previous encounters. In Drosophila, the mushroom bodies (MBs) are critical for olfactory associative learning and conditioned taste aversion, but how the output of the MBs affects specific behavioral responses is unresolved. In conditioned taste aversion, Drosophila shows a specific behavioral change upon learning: proboscis extension to sugar is reduced after a sugar stimulus is paired with an aversive stimulus. While studies have identified MB output neurons (MBONs) that drive approach or avoidance behavior, whether the same MBONs impact innate proboscis extension behavior is unknown. Here, we tested the role of MB pathways in altering proboscis extension and identified MBONs that synapse onto multiple MB compartments that upon activation significantly decreased proboscis extension to sugar. Activating several of these lines also decreased sugar consumption, revealing that these MBONs have a general role in modifying feeding behavior beyond proboscis extension. The MBONs that decreased proboscis extension and ingestion are different from those that drive avoidance behavior in another context. These studies provide insight into how activation of MB output neurons decreases proboscis extension to taste compounds.

RevDate: 2021-05-02
CmpDate: 2020-09-22

Derman RC, Bass CE, CR Ferrario (2020)

Effects of hM4Di activation in CamKII basolateral amygdala neurons and CNO treatment on sensory-specific vs. general PIT: refining PIT circuits and considerations for using CNO.

Psychopharmacology, 237(5):1249-1266.

BACKGROUND: Pavlovian stimuli can influence instrumental behaviors via phenomena such as Pavlovian-to-instrumental transfer (PIT). PIT arises via dissociable processes as sensory-specific PIT (SS-PIT) and general PIT. The basolateral amygdala (BLA) mediates SS-PIT, but not general PIT. However, the specific BLA neuronal populations involved are unknown.

AIMS: To determine the contribution of glutamatergic BLA neurons to the expression of SS-PIT and to the recall of sensory-specific properties of stimulus-outcome associations.

METHODS: BLA neurons were transduced with virus containing either GFP or hM4Di, driven by the CamKII promoter. Rats were then tested for SS and general PIT and subsequently for expression of Pavlovian outcome devaluation effects and conditioned taste aversion following injections of vehicle or clozapine-N-oxide (CNO, the hM4Di agonist).

RESULTS: CNO selectively blocked SS-PIT in the hM4Di-expressing group, but not controls, without altering expression of Pavlovian outcome devaluation or sensory-specific taste aversion in either group. Unexpectedly, CNO disrupted general PIT in both groups.

CONCLUSIONS: CamKII BLA neurons mediate the expression of SS-PIT by enabling Pavlovian stimuli to trigger recall of the correct action-outcome associations rather than by mediating recall of the sensory-specific properties of the stimulus-outcome association. Separately, our data demonstrate that CNO alone is sufficient to disrupt affective, but not sensory-specific processes, an effect that was not due to generalized motor disruption. This non-specific effect on general PIT may be related to CNO-induced shifts in internal state. Together, these data identify BLA CamKII neurons as critical for the expression of SS-PIT and reveal important considerations for using CNO to study general affective motivation.

RevDate: 2020-10-01

Liu DW, Ma L, Zhang XH, et al (2019)

Conditioned taste aversion memory extinction temporally induces insular cortical BDNF release and inhibits neuronal apoptosis.

Neuropsychiatric disease and treatment, 15:2403-2414.

Background: Memory extinction has been reported to be related to psychiatric disorders, such as post-traumatic stress disorder (PTSD). Secretion and synthesis of brain-derived neurotrophic factor (BDNF) have been shown to temporally regulate various memory processes via activation of tropomyosin-related kinase B (TrkB) receptors. However, whether memory extinction induces the synthesis and secretion of BDNF on the basis of its localization is not understood. In this study, we aim to investigate activity-dependent BDNF secretion and synthesis in the insular cortex (IC) in the setting of conditioned taste aversion (CTA) memory extinction.

Materials and methods: Rats were subjected to CTA memory extinction and BDNF antibody (or the equal volume of vehicle) was microinjected into the IC immediately after the extinction testing. Real-time polymerase chain reaction and in situ hybridization were used to detect the gene expression of BDNF, NGF and NT4. The protein levels of BDNF were determined through the enzyme-linked immunosorbent assay. In addition, the levels of phosphorylated TrkB normalized to total TrkB were evaluated using immunoprecipitation and immunoblotting. c-Fos, total extracellular signal-regulated kinase (Erk), phosphorylated Erk, and apoptosis-related protein (caspase-3), were detected by Western blotting.

Results: We found that blocking BDNF signaling within the IC disrupts CTA extinction, suggesting that BDNF signaling in the IC is necessary for CTA extinction. Increased expression levels of c-Fos indicate the induced neuronal activity in the IC during CTA extinction. In addition, temporal changes in the gene expression and protein levels of BDNF in the IC were noted during extinction. Moreover, we found that phosphorylation of TrkB increased prior to the enhanced BDNF expression, suggesting that CTA extinction induces rapid activity-dependent BDNF secretion in the IC. Finally, we found decreased expression of caspase-3 in the IC after CTA extinction.

Conclusion: These results demonstrate that CTA memory extinction temporally induces the release and synthesis of BDNF in the IC and inhibits neuronal apoptosis.

RevDate: 2021-03-02
CmpDate: 2021-01-19

Bouton ME, Broomer MC, Rey CN, et al (2020)

Unexpected food outcomes can return a habit to goal-directed action.

Neurobiology of learning and memory, 169:107163.

Three experiments examined the return of a habitual instrumental response to the status of goal-directed action. In all experiments, rats received extensive training in which lever pressing was reinforced with food pellets on a random-interval schedule of reinforcement. In Experiment 1, the extensively-trained response was not affected by conditioning a taste aversion to the reinforcer, and was therefore considered a habit. However, if the response had earned a new and unexpected food pellet during the final training session, the response was affected by taste aversion conditioning to the (first) reinforcer, and had thus been converted to a goal-directed action. In Experiment 3, 30 min of prefeeding with an irrelevant food pellet immediately before the test also converted a habit back to action, as judged by the taste-aversion devaluation method. That result was consistent with difficulty in finding evidence of habit with the sensory-specific satiety method after extensive instrumental training (Experiment 2). The results suggest that an instrumental behavior's status as a habit is not permanent, and that a habit can be returned to action status by associating it with a surprising reinforcer (Experiment 1) or by giving the animal an unexpected prefeeding immediately prior to the action/habit test (Experiment 3).

RevDate: 2021-03-02
CmpDate: 2021-01-19

Trask S, Shipman ML, Green JT, et al (2020)

Some factors that restore goal-direction to a habitual behavior.

Neurobiology of learning and memory, 169:107161.

Recent findings from our laboratory suggest that an extensively-practiced instrumental behavior can appear to be a goal-directed action (rather than a habit) when a second behavior is added and reinforced during intermixed final sessions (Shipman et al., 2018). The present experiments were designed to explore and understand this finding. All used the taste aversion method of devaluing the reinforcer to distinguish between goal-directed actions and habits. Experiment 1 confirmed that reinforcing a second response in a separate context (but not mere exposure to that context) can return an extensively-trained habit to the status of goal-directed action. Experiment 2 showed that training of the second response needs to be intermixed with training of the first response to produce this effect; training the second response after the first-response training was complete preserved the first response as a habit. Experiment 3 demonstrated that reinforcing the second response with a different reinforcer breaks the habit status of the first response. Experiment 4 found that free reinforcers (that were not response-contingent) were sufficient to restore goal-directed performance. Together, the results suggest that unexpected reinforcer delivery can render a habitual response goal-directed again.

RevDate: 2020-09-07
CmpDate: 2020-09-07

Alapin JM, Dines M, R Lamprecht (2020)

EphB2 receptor forward signaling is needed for normal long-term memory formation in aged mice.

Neurobiology of aging, 86:11-15.

The molecular mechanisms underpinning age-related changes in the ability to form long-term memory need to be clarified. EphB2 receptors and their ephrin ligands are involved in key cellular functions such as neuronal morphogenesis and synaptic transmission believed to be involved in long-term memory formation. We were therefore interested to explore whether EphB2 is involved in the alterations in memory formation abilities observed in old age. Toward that end, we examined the ability to form long-term memory in mice that lack EphB2 (EphB2-/-). A previous study has shown that the ability to form long-term conditioned taste aversion (CTA) memory in young EphB2-/- mice remains intact. In the present study, we report that long-term CTA memory formation is improved in old wild-type mice but not in age-matched old EphB2-/- mice. To further explore EphB2 mechanisms responsible for this difference in memory formation ability, we examined CTA memory in EphB2lacZ/lacZ mice devoid of EphB2 forward signaling. We found that the ability to create CTA long-term memory is unaffected in young EphB2lacZ/lacZ mice. However, the ability to form an increased long-term CTA memory shown in old wild-type mice is impaired in old EphB2lacZ/lacZ mice. The inability to form enhanced CTA long-term memory in EphB2-/- and EphB2lacZ/lacZ old mice was not caused by differences in taste perception or ability to consume fluids. Thus, our observations show that the absence of EphB2 forward signaling in old mice impairs the ability to form enhanced long-term CTA memory and indicate that EphB2 forward signaling is needed for normal memory formation in aged mice.

RevDate: 2021-02-01
CmpDate: 2020-08-03

Keefer SE, GD Petrovich (2020)

The basolateral amygdala-medial prefrontal cortex circuitry regulates behavioral flexibility during appetitive reversal learning.

Behavioral neuroscience, 134(1):34-44.

Environmental cues can become predictors of food availability through Pavlovian conditioning. Two forebrain regions important in this associative learning are the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). Recent work showed the BLA-mPFC pathway is activated when a cue reliably signals food, suggesting the BLA informs the mPFC of the cue's value. The current study tested this hypothesis by altering the value of 2 food cues using reversal learning and illness-induced devaluation paradigms. Rats that received unilateral excitotoxic lesions of the BLA and mPFC contralaterally placed, along with ipsilateral and sham controls, underwent discriminative conditioning, followed by reversal learning and then devaluation. All groups successfully discriminated between 2 auditory stimuli that were followed by food delivery (conditional stimulus [CS] +) or not rewarded (CS-), demonstrating this learning does not require BLA-mPFC communication. When the outcomes of the stimuli were reversed, the rats with disconnected BLA-mPFC (contralateral condition) showed increased responding to the CSs, especially to the rCS + (original CS-) during the first session, suggesting impaired cue memory recall and behavioral inhibition compared to the other groups. For devaluation, all groups successfully learned conditioned taste aversion; however, there was no evidence of cue devaluation or differences between groups. Interestingly, at the end of testing, the nondevalued contralateral group was still responding more to the original CS + (rCS-) compared to the devalued contralateral group. These results suggest a potential role for BLA-mPFC communication in guiding appropriate responding during periods of behavioral flexibility when the outcomes, and thus the values, of learned cues are altered. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

RevDate: 2021-04-08
CmpDate: 2020-07-20

Torruella-Suárez ML, Vandenberg JR, Cogan ES, et al (2020)

Manipulations of Central Amygdala Neurotensin Neurons Alter the Consumption of Ethanol and Sweet Fluids in Mice.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 40(3):632-647.

The central nucleus of the amygdala plays a significant role in alcohol use and other affective disorders; however, the genetically-defined neuronal subtypes and projections that govern these behaviors are not well known. Here we show that neurotensin neurons in the central nucleus of the amygdala of male mice are activated by in vivo ethanol consumption and that genetic ablation of these neurons decreases ethanol consumption and preference in non-ethanol-dependent animals. This ablation did not impact preference for sucrose, saccharin, or quinine. We found that the most robust projection of the central amygdala neurotensin neurons was to the parabrachial nucleus, a brain region known to be important in feeding behaviors, conditioned taste aversion, and alarm. Optogenetic stimulation of projections from these neurons to the parabrachial nucleus is reinforcing, and increases ethanol drinking as well as consumption of sucrose and saccharin solutions. These data suggest that this central amygdala to parabrachial nucleus projection influences the expression of reward-related phenotypes and is a novel circuit promoting consumption of ethanol and palatable fluids.SIGNIFICANCE STATEMENT Alcohol use disorder (AUD) is a major health burden worldwide. Although ethanol consumption is required for the development of AUD, much remains unknown regarding the underlying neural circuits that govern initial ethanol intake. Here we show that ablation of a population of neurotensin-expressing neurons in the central amygdala decreases intake of and preference for ethanol in non-dependent animals, whereas the projection of these neurons to the parabrachial nucleus promotes consumption of ethanol as well as other palatable fluids.

RevDate: 2021-01-22
CmpDate: 2021-01-22

Basu S, Alapin JM, Dines M, et al (2020)

Long-term memory is maintained by continuous activity of Arp2/3 in lateral amygdala.

Neurobiology of learning and memory, 167:107115.

Evidence indicates that long-term memory formation involves alterations in synaptic efficacy produced by modifications in neural transmission and morphology. However, it is not clear how such changes induced by learning, that encode memory, are maintained over long period of time to preserve long-term memory. It has been shown that the actin nucleating protein Arp2/3 is essential for supporting neuronal morphology and synaptic transmission. We therefore hypothesized that continuous Arp2/3 activity is needed to maintain long-term memory over time. To test this hypothesis we microinjected into lateral amygdala (LA) of rats CK-666, a specific inhibitor of Arp2/3, two days after fear conditioning and tested the effect on long-term fear memory maintenance a day afterward. We found that injection of CK-666 two days after training abolished fear conditioning memory. Fear conditioning could be formed when a control compound CK-689 was applied two days after training. Microinjection of CK-666 a day before fear conditioning training had no effect on fear conditioning learning and long-term memory formation. We revealed that Arp2/3 is also needed to maintain long-term conditioned taste aversion (CTA) memory in LA. Microinjection of CK-666 two days after CTA training impaired long-term memory tested a day afterwards. We conclude that continuous activity of Arp2/3 in LA is essential for the maintenance of long-term memory.

RevDate: 2020-07-13
CmpDate: 2020-07-13

Ali J, Chiang M, Lee JB, et al (2020)

Is rat a good model for assessment of particulate-based taste-masked formulations?.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, 146:1-9.

Recently there has been an increased interest to develop specialised dosage forms that are better suited to specific patient populations, such as paediatrics and geriatrics. In these patient populations the acceptability of the oral dosage form can be paramount to the products success. However, many Active Pharmaceutical Ingredients (APIs) are known to cause an aversive taste response. One way to increase the acceptability and to enhance the palatability of the formulation is to design coated taste-masked particulate-based dosage forms. The masking of poorly tasting drugs with physical barriers such as polymer coatings can be utilised to prevent the release of drug within the oral cavity, thus preventing a taste response. However, currently, there are few assessment tools and models available to test the efficiency of these particulate-based taste-masked formulations. The rat brief access taste aversion model has been shown to be useful in assessment of taste for liquid dosage forms. However, the applicability of the rat model for particulate-based taste masked formulations is yet to be assessed. It is not understood whether dissolution, solubility and thus exposure of the drug to taste receptors would be the same in rat and human. Therefore, rat saliva must be compared to human saliva to determine the likelihood that drug release would be similar within the oral cavity for both species. In this study rat saliva was characterised for parameters known to be important for drug dissolution, such as pH, buffer capacity, surface tension, and viscosity. Subsequently dissolution of model bitter tasting compounds, sildenafil citrate and efavirenz, in rat saliva was compared to dissolution in human saliva. For all parameters characterised and for the dissolution of both drugs in rat saliva, a substantial difference was observed when compared to human saliva. This discrepancy in saliva parameters and dissolution of model drugs suggests that preclinical taste evaluation of particulate-based taste-masked formulations suggests rat is not a good model for predicting taste of solid dosage forms or undissolved drug where dissolution is required. Alternative preclinical in vivo models in other species, or improved biorelevant in vitro models should be considered instead.

RevDate: 2020-09-21
CmpDate: 2020-09-21

Song L, Chen K, Yan J, et al (2019)

Maternal high-fat diet during gestation and lactation increases conditioned aversion threshold for sucrose and alters sweet taste receptors expression in taste buds in rat offspring.

Physiology & behavior, 212:112709.

Maternal high-fat (HF) diet affects offspring's metabolic phenotype. Sweet taste is an important factor in promoting appetite. In order to determine the effects of maternal HF diet throughout gestation and lactation on taste sensitivity to sucrose in rat offspring, we measured conditioned aversion threshold for sucrose by conditioned taste aversion (CTA) associated with two-bottle choice tests, and measured mRNA expression of sweet taste receptors in taste buds. In male offspring, conditioned aversion threshold for sucrose lay between 0.007 M and 0.009 M in control group, while in those with HF dams, the threshold significantly increased to be between 0.011 M and 0.02 M. In female offspring, conditioned aversion threshold for sucrose lay between 0.003 M and 0.005 M in control group, whereas maternal HF diet increased it to be between 0.007 M and 0.009 M. Maternal HF diet increased T1R2 and T1R3 mRNA expression in taste buds of male offspring, while only increased T1R2 mRNA expression in female offspring. Both male and female offspring with HF dams had lower α-gustducin mRNA expression, whereas only male offspring with HF dams had lower OB-Rb mRNA expression in taste buds. Our data suggest that maternal HF diet decreased taste sensitivity to sucrose in both male and female offspring, which may be partly due to altered expression of sweet taste receptors and related downstream pathways in taste buds.

RevDate: 2020-07-01
CmpDate: 2020-07-01

Kayyal H, Yiannakas A, Kolatt Chandran S, et al (2019)

Activity of Insula to Basolateral Amygdala Projecting Neurons is Necessary and Sufficient for Taste Valence Representation.

The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(47):9369-9382.

Conditioned taste aversion (CTA) is an associative learning paradigm, wherein consumption of an appetitive tastant (e.g., saccharin) is paired to the administration of a malaise-inducing agent, such as intraperitoneal injection of LiCl. Aversive taste learning and retrieval require neuronal activity within the anterior insula (aIC) and the basolateral amygdala (BLA). Here, we labeled neurons of the aIC projecting to the BLA in adult male mice using a retro-AAV construct and assessed their necessity in aversive and appetitive taste learning. By restricting the expression of chemogenetic receptors in aIC-to-BLA neurons, we demonstrate that activity within the aIC-to-BLA projection is necessary for both aversive taste memory acquisition and retrieval, but not for its maintenance, nor its extinction. Moreover, inhibition of the projection did not affect incidental taste learning per se, but effectively suppressed aversive taste memory retrieval when applied either during or before the encoding of the unconditioned stimulus for CTA (i.e., malaise). Remarkably, activation of the projection after novel taste consumption, without experiencing any internal discomfort, was sufficient to form an artificial aversive taste memory, resulting in strong aversive behavior upon retrieval. Our results indicate that aIC-to-BLA projecting neurons are an essential component in the ability of the brain to associate taste sensory stimuli with body states of negative valence and guide the expression of valence-specific behavior upon taste memory retrieval.SIGNIFICANCE STATEMENT In the present study we subjected mice to the conditioned taste aversion paradigm, where animals learn to associate novel taste with malaise (i.e., assign it negative valence). We show that activation of neurons in the anterior insular cortex (aIC) that project into the basolateral amygdala (BLA) in response to conditioned taste aversion is necessary to form a memory for a taste of negative valence. Moreover, artificial activation of this pathway (without any feeling of pain) after the sampling of a taste can also lead to such associative memory. Thus, activation of aIC-to-BLA projecting neurons is necessary and sufficient to form and retrieve aversive taste memory.

RevDate: 2020-11-05
CmpDate: 2020-11-05

Har-Paz I, Roisman N, Michaelson DM, et al (2019)

Extra-Hippocampal Learning Deficits in Young Apolipoprotein E4 Mice and Their Synaptic Underpinning.

Journal of Alzheimer's disease : JAD, 72(1):71-82.

The E4 allele of apolipoprotein (apoE4) is the primary genetic risk factor for late onset Alzheimer's disease (AD), yet the exact manner in which apoE4 leads to the development of AD is undetermined. Human and animal studies report that apoE4-related memory deficits appear earlier than the AD clinical manifestation, thus suggesting the existence of early, pre-pathological, apoE4 impairments that may later lead to AD onset. While current research regards the hippocampus as the initial and primary effected locus by apoE4, we presently investigate the possibility that apoE4 innately impairs any brain area that requires synaptic plasticity. To test this hypothesis, we trained young (3-4-month-old) target-replacement apoE3 and apoE4 mice in conditioned taste aversion (CTA) acquisition and extinction learnings- hippocampus-independent learnings that are easily performed at a young age. Synaptic vesicular markers analysis was conducted in the gustatory cortex (GC), basolateral amygdala (BLA), medial prefrontal cortex (mPFC), and hippocampal CA3 to reveal underlying apoE4-related impairments. We have found that young apoE4 mice are severely impaired in CTA acquisition and extinction learning. CTA acquisition impairments were correlated with reduced vGat and vGlut levels in the BLA and GC, but not in the CA3. CTA extinction was correlated with lower synaptophysin and vGlut levels in the mPFC, a central region in CTA extinction. Our results support apoE4-related early-life plasticity impairments that precede the AD clinical manifestations and affect any brain area that depends on extensive plasticity; early impairments that may promote the development of AD pathologies later in life.

RevDate: 2020-07-28
CmpDate: 2020-07-28

He ABH, Huang CL, Kozłowska A, et al (2019)

Involvement of neural substrates in reward and aversion to methamphetamine addiction: Testing the reward comparison hypothesis and the paradoxical effect hypothesis of abused drugs.

Neurobiology of learning and memory, 166:107090.

Clinical studies of drug addiction focus on the reward impact of abused drugs that produces compulsive drug-seeking behavior and drug dependence. However, a small amount of research has examined the opposite effect of aversion to abused drugs to balance the reward effect for drug taking. An aversive behavioral model of abused drugs in terms of conditioned taste aversion (CTA) was challenged by the reward comparison hypothesis (Grigson, 1997). To test the reward comparison hypothesis, the present study examined the rewarding or aversive neural substrates involved in methamphetamine-induced conditioned suppression. The behavioral data showed that methamphetamine induced conditioned suppression on conditioning and reacquisition but extinguished it on extinction. A higher level of stressful aversive corticosterone occurred on conditioning and reacquisition but not extinction. The c-Fos or p-ERK immunohistochemical activity showed that the cingulated cortex area 1 (Cg1), infralimbic cortex (IL), prelimbic cortex (PrL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) of the hippocampus were overexpressed in aversive CTA induced by methamphetamine. These data may indicate that the Cg1, IL, PrL, BLA, NAc, and DG probably mediated the paradoxical effect-reward and aversion. Altogether, our data conflicted with the reward comparison hypothesis, and methamphetamine may simultaneously induce the paradoxical effect of reward and aversion in the brain to support the paradoxical effect hypothesis of abused drugs. The present data implicate some insights for drug addiction in clinical aspects.

RevDate: 2020-02-05
CmpDate: 2020-02-05

Nakajima S (2019)

Further demonstration of running-based food avoidance learning in laboratory mice (Mus musculus).

Behavioural processes, 168:103962.

Voluntary wheel running has hedonically bivalent properties in laboratory rats and mice. While it works as a reward for instrumental performance such as bar pressing, it also functions as an aversive stimulus to establish Pavlovian conditioned avoidance of the paired stimulus. The present study focused on the latter case. Running in closed wheels hampered habituation of a reluctance to eat a target snack in rats (Experiment 1A) and mice (Experiment 1B) trained by pairing access to a target snack with confinement to a wheel attached to the cage. Experiment 2 successfully confirmed and extended this finding with mice running in both open and closed wheels. A differential conditioning procedure employed in Experiment 3 ensured that this phenomenon is specific to the snack paired with running, implying that it reflects Pavlovian conditioned flavor avoidance (CFA). Free exploration in cages without wheels, however, did not results in a CFA.

RevDate: 2020-09-17
CmpDate: 2020-09-17

Osorio-Gómez D, Bermúdez-Rattoni F, K Guzmán-Ramos (2019)

Artificial taste avoidance memory induced by coactivation of NMDA and β-adrenergic receptors in the amygdala.

Behavioural brain research, 376:112193.

The association between a taste and gastric malaise allows animals to avoid the ingestion of potentially toxic food. This association has been termed conditioned taste aversion (CTA) and relies on the activity of key brain structures such as the amygdala and the insular cortex. The establishment of this gustatory-avoidance memory is related to glutamatergic and noradrenergic activity within the amygdala during two crucial events: gastric malaise (unconditioned stimulus, US) and the post-acquisition spontaneous activity related to the association of both stimuli. To understand the functional implications of these neurochemical changes on avoidance memory formation, we assessed the effects of pharmacological stimulation of β-adrenergic and glutamatergic NMDA receptors through the administration of a mixture of L-homocysteic acid and isoproterenol into the amygdala after saccharin exposure on specific times to emulate the US and post-acquisition local signals that would be occurring naturally under CTA training. Our results show that activation of NMDA and β-adrenergic receptors generated a long-term avoidance response to saccharin, like a naturally induced rejection with LiCl. Moreover, the behavioral outcome was accompanied by changes in glutamate, norepinephrine and dopamine levels within the insular cortex, analogous to those displayed during memory retrieval of taste aversion memory. Therefore, we suggest that taste avoidance memory can be induced artificially through the emulation of specific amygdalar neurochemical signals, promoting changes in the amygdala-insular cortex circuit enabling memory establishment.

RevDate: 2020-09-30

Cunningham CL (2019)

Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains.

Brain sciences, 9(8):.

The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol's aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders.

RevDate: 2020-06-04
CmpDate: 2020-06-04

Galistu A, PS D'Aquila (2020)

Daily memantine treatment blunts hedonic response to sucrose in rats.

Psychopharmacology, 237(1):103-114.

RATIONALE: Preclinical and clinical studies suggest the potential use of memantine in the treatment of binge eating disorder. The aim of this study was to further investigate the mechanisms by which memantine influences the motivational aspects of ingestion through the analysis of licking microstructure. To interpret treatment effects in relation to drug action at specific functionally relevant times, we compared the effect of two different administration schedules.

METHODS: Memantine was administered daily for a week, either 1 h before or immediately after a 30-min daily session. The effects on the microstructure of licking for a 10% sucrose solution in rats were examined in the course of treatment and for 15 days after treatment discontinuation.

RESULTS: Treatment before testing reduced ingestion due to reduced burst size and increased latency in the first session. However, a progressive increase in burst number across sessions led to a full recovery of ingestion levels by the end of treatment. Daily post-session administration induced a dramatic decrease of activation of licking behaviour, indicated by reduced burst number, accompanied to reduced burst size. A slow recovery of ingestion took place after treatment discontinuation.

CONCLUSION: These results suggest a reduced hedonic/reward evaluation response, an effect likely due to NMDA receptor blockade occurring during the testing time and support the hypothesis that memantine interferes with the hedonic/non-homeostatic mechanisms regulating food intake and food-seeking. The effect of post-session administration might be explained by the development of conditioned taste aversion.

RevDate: 2021-01-10
CmpDate: 2020-04-02

Wills AJ, Edmunds CER, Le Pelley ME, et al (2019)

Dissociable learning processes, associative theory, and testimonial reviews: A comment on Smith and Church (2018).

Psychonomic bulletin & review, 26(6):1988-1993.

Smith and Church (Psychonomic Bulletin & Review, 25, 1565-1584 2018) present a "testimonial" review of dissociable learning processes in comparative and cognitive psychology, by which we mean they include only the portion of the available evidence that is consistent with their conclusions. For example, they conclude that learning the information-integration category-learning task with immediate feedback is implicit, but do not consider the evidence that people readily report explicit strategies in this task, nor that this task can be accommodated by accounts that make no distinction between implicit and explicit processes. They also consider some of the neuroscience relating to information-integration category learning, but do not report those aspects that are more consistent with an explicit than an implicit account. They further conclude that delay conditioning in humans is implicit, but do not report evidence that delay conditioning requires awareness; nor do they present the evidence that conditioned taste aversion, which should be explicit under their account, can be implicit. We agree with Smith and Church that it is helpful to have a clear definition of associative theory, but suggest that their definition may be unnecessarily restrictive. We propose an alternative definition of associative theory and briefly describe an experimental procedure that we think may better distinguish between associative and non-associative processes.

RevDate: 2020-10-01
CmpDate: 2020-04-06

Harris AC, Muelken P, Swain Y, et al (2019)

Non-nicotine constituents in e-cigarette aerosol extract attenuate nicotine's aversive effects in adolescent rats.

Drug and alcohol dependence, 203:51-60.

BACKGROUND: Development of preclinical methodology for evaluating the abuse liability of electronic cigarettes (ECs) in adolescents is urgently needed to inform FDA regulation of these products. We previously reported reduced aversive effects of EC liquids containing nicotine and a range of non-nicotine constituents (e.g., propylene glycol, minor tobacco alkaloids) compared to nicotine alone in adult rats as measured using intracranial self-stimulation. The goal of this study was to compare the aversive effects of nicotine alone and EC aerosol extracts in adolescent rats as measured using conditioned taste aversion (CTA), which can be conducted during the brief adolescent period.

METHODS AND RESULTS: In Experiment 1, nicotine alone (1.0 or 1.5 mg/kg, s.c.) produced significant CTA in adolescent rats in a two-bottle procedure, thereby establishing a model to study the effects of EC extracts. At a nicotine dose of 1.0 mg/kg, CTA to Vuse Menthol EC extract, but not Aroma E-Juice EC extract, was attenuated compared to nicotine alone during repeated two-bottle CTA tests (Experiment 2a). At a nicotine dose of 0.5 mg/kg, CTA to Vuse Menthol EC extract did not differ from nicotine alone during the first two-bottle CTA test but extinguished more rapidly across repeated two-bottle tests (Experiment 2b).

CONCLUSIONS: Non-nicotine constituents in Vuse Menthol EC extracts attenuated CTA in a two-bottle procedure in adolescents. This model may be useful for anticipating the abuse liability of ECs in adolescents and for modeling FDA-mandated changes in product standards for nicotine or other constituents in ECs.

RevDate: 2019-11-25
CmpDate: 2019-11-25

Cui Y, Wu H, Li Q, et al (2019)

Impairment of Bitter Taste Sensor Transient Receptor Potential Channel M5-Mediated Aversion Aggravates High-Salt Intake and Hypertension.

Hypertension (Dallas, Tex. : 1979), 74(4):1021-1032.

Excessive salt consumption leads to cardiovascular diseases. Despite various measures designed to reduce salt intake, daily salt intake remains at a high level. Appropriate salt intake is balanced by salt taste preference triggered by epithelium sodium channel and salt taste aversion evoked by bitter taste sensor, transient receptor potential channel M5 (TRPM5). However, the behavioral mechanism of excessive salt intake remains largely elusive. In this study, wild type and TRPM5-/- mice were applied to study the influence of high-salt administration on epithelium sodium channel/TRPM5 and the associated behavior to salt consumption. We found that long-term high-salt intake impaired the aversive behavior to high-salt stimulation but did not alter the preference to low salt in mice. The mechanistic evidence demonstrated that high-salt intake blunted the TRPM5-mediated aversive behavior to noxious salt stimulation through inhibiting PKC (protein kinase C) activity and PKC-dependent threonine phosphorylation in the tongue epithelium but did not affect the epithelium sodium channel-dependent salt taste preference. Inhibition of TRPM5 also resulted in an impaired aversive response to high salt, with reduced taste perception in bitter cortical field of mice. TRPM5-/- mice showed a lowered aversion to high-salt diet and developed salt-induced hypertension. The impaired perception to bitter taste evoked by high-salt intake also existed in hypertensive patients with high-salt consumption. We demonstrate that long-term high-salt consumption impairs aversive response to concentrated salt by downregulating bitter taste sensor TRPM5. It suggests that enhancing TRPM5 function might antagonize excessive salt intake and high salt-induced hypertension.

RevDate: 2020-10-01

Ruiz F, Keeley A, Léglise P, et al (2019)

Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.

Pharmaceutics, 11(8):.

Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer's medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa®, tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa® (n = 54), the oral formulation sub-group was classified as "negatively accepted", while the coated tablet was associated with the "positively accepted" cluster. In men, both formulations belonged to the "positively accepted" profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.

RevDate: 2020-04-08
CmpDate: 2020-04-08

Olvera MJ, MI Miranda (2019)

Specific inter-stimulus interval effect of NMDA receptor activation in the insular cortex during conditioned taste aversion.

Neurobiology of learning and memory, 164:107043.

Taste memory recognition is crucial for species survival; thus, the acquisition of conditioned taste aversion (CTA) protects animals against consuming poisons or toxins. In nature, food and poison are confined in the same edible item; however, in the laboratory these food constituents are usually presented separately for experimental analysis. The taste, or conditioned stimulus (CS), can be hours apart from the gastric malaise, or unconditioned stimulus (US); this extended inter-stimulus interval (ISI) allows the analysis of a particular learning phase. Evidence indicates a relevant function of glutamatergic activity in the insular cortex (IC) throughout the ISI. N-methyl-D-aspartate receptors (NMDAR) are crucial during CTA acquisition and retrieval. However, the exact participation of NMDAR in the IC during the ISI has not been demonstrated. Thus, the aim of this work was to evaluate the effects of temporal NMDAR activation during four time frames throughout the ISI of conditioned sugar aversion with bilateral injections of NMDA at a physiological dose (1 µg/µl) in the IC, given (1) immediately before or (2) immediately after sugar presentation, or (3) immediately before or (4) immediately after LiCl i.p. injection. The results showed that NMDAR activation in the IC had a specific ISI effect during CTA acquisition, increasing aversive memory formation and delaying extinction only after CS presentation. Overall, these results demonstrate that NMDAR in the IC have a particular enhancing associative effect after CS and suggest that there is a precise coincidence in neurochemical events in the IC that correlates with the stimulus to be associated and the glutamate NMDAR activity that must be finely tuned in the ISI during CTA acquisition.

RevDate: 2019-12-02
CmpDate: 2019-12-02

Tobajas J, Gómez-Ramírez P, María-Mojica P, et al (2019)

Selection of new chemicals to be used in conditioned aversion for non-lethal predation control.

Behavioural processes, 166:103905.

Globally, native predators and scavengers are threatened through the incidence of illegal poisoning due to increasing human-wildlife conflicts. The use of conditioned taste aversion (CTA) may mitigate such conflicts. CTA is a robust learning paradigm that occurs when animals associate a food with a discomfort induced by a chemical, thereby avoiding that food in subsequent encounters. We reviewed the potential of 167 chemical compounds to be used in CTA, considering effects, margin of safety, accessibility, and detectability. After the review, 15 compounds fulfilled the required characteristics, but only five (thiabendazole, thiram, levamisole, fluconazole and fluralaner) were finally selected to be tested in CTA assays with dogs. Of the tested compounds, thiabendazole, thiram and levamisole caused target food rejection by dogs and reduced the time spent eating during post-conditioning. However, despite being microencapsulated, levamisole appeared to be detectable by dogs, whereas thiram and thiabendazole were not. Fluconazole and fluralaner did not produce any CTA effect. Thiabendazole, thiram and levamisole can therefore induce CTA, and thus are potential candidates as aversive compounds for wildlife management. Thiram is an undetectable, relatively safe and accessible compound that can induce CTA in canids, and opens new possibilities to develop methods of non-lethal predation control.

RevDate: 2020-04-15
CmpDate: 2020-04-15

Tobajas J, Gómez-Ramírez P, Ferreras P, et al (2020)

Conditioned food aversion in domestic dogs induced by thiram.

Pest management science, 76(2):568-574.

BACKGROUND: The conflict between predators and humans for resources such as game species or livestock is an ancient issue, and it is especially sharp in the case of medium-large wild canids. In order to manage this conflict, lethal control methods are often used, which can sometimes be illegal, such as poisoning. As an alternative, conditioned food aversion (CFA) is a non-lethal method to reduce predation in which animals learn to avoid a given food due to the adverse effects caused by the ingestion of an undetectable chemical compound added to this food. The present study aimed to test thiram as a CFA agent in penned dogs as a first approach to use this substance for reducing the predation conflict associated with wild canids.

RESULTS: Thiram, with or without an additional odor cue, produced CFA in penned dogs for more than 2 months. Moreover, thiram seemed to be undetectable and safe after the third ingestion of a 40-60 mg kg-1 dose. Desirable adverse effects, such as vomits, appeared around 1 h after exposure. These characteristics make thiram optimal for its use in predation reduction through CFA. However, individual variability could prevent CFA acquisition by some animals.

CONCLUSIONS: Thiram has the potential to be used as a CFA agent in wildlife management and conservation to reduce predation by wild canids. Since thiram produced CFA without the problems of detectability and toxicity caused by other substances, it may be an alternative to lethal control methods used to reduce predation on game, livestock and endangered species. © 2019 Society of Chemical Industry.

RevDate: 2019-09-06
CmpDate: 2019-09-05

Li LM, Liao YY, ES Jiang (2019)

[The electrophysiological response of chorda tympani nerve to taste stimuli in rats with conditioned taste aversion to saltiness].

Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology, 35(3):239-244.

OBJECTIVE: To explore the characteristic changes of the peripheral chorda tympanic nerve (CT) electrophysiological responses to salty stimulus and other taste stimuli in rats with the conditioned taste aversion to saltiness.

METHODS: Fourteen adult SD male rats were divided into a conditioned taste aversion to salty group (CTA) and a control group (Ctrl) (n=7/group). On the first day of the experiment, rats were given a 0.1 mol/L NaCl intake for 30 min, then, the rats in CTA and Ctrl groups were injected intraperitoneally with 2 ml of 0.15 mol/L LiCl and the same amount of saline respectively. On day 2, 3 and 4, the 30 min consumption of NaCl and distilled water was measured for both groups of rats. On the 4th day after the behavioral test of that day, CT electrophysiological recording experiments were performed on CTA rats and control rats.

RESULTS: Compared with the rats in Ctrl group, the electrophysiological characteristics of CT in CTA group rats did not change significantly the responses to the series of NaCl and other four basic taste stimuli (P>0.05). The amiloride, the epithelial sodium channel blocker, strongly inhibited the response of CT to NaCl in CTA and Ctrl group rats (P<0.01).

CONCLUSION: The electrophysiological responses of CT to various gustatory stimuli do not significantly change in rats after the establishment of conditional taste aversion to the saltiness.

RevDate: 2020-03-09
CmpDate: 2020-03-05

Inui T, Sugishita T, Inui-Yamamoto C, et al (2019)

The Basolateral Nucleus of the Amygdala Executes the Parallel Processes of Avoidance and Palatability in the Retrieval of Conditioned Taste Aversion in Male Rats.

eNeuro, 6(4):.

Conditioned taste aversion (CTA) is an essential behavior for animal survival. Conditioned animals show avoidance and decreased palatability to a conditioned stimulus (CS) on CTA retrieval. In this study, we aimed to determine whether the basolateral nucleus of the amygdala (BLA) is involved in CTA retrieval and whether avoidance and palatability in CTA retrieval are processed in the BLA. We developed an experimental chamber for time-course analysis of the behavior to approach a spout and lick a CS. In this experimental chamber, we analyzed the behavior of male rats following microinjections of GABAA receptor agonist muscimol or saline into the BLA. The rats showed two types of approach behavior: they either (1) approached and licked the spout or (2) approached but did not lick the spout. Muscimol injection into the BLA decreased the frequency of the latter type of approach behavior, indicating that BLA inactivation reduced avoidance to the CS. The muscimol injection into the BLA also significantly increased the consumption of the CS. Lick microstructure analysis demonstrated that intra-BLA muscimol significantly increased licking burst number and size, indicating that BLA inactivation attenuated aversion to the CS as large burst licking is an indicator of high palatability. These results suggest that the increase in CS consumption with intra-BLA muscimol injection was due to alterations in approach and aversive responses to the CS. Therefore, we conclude that the BLA plays an essential role in CTA retrieval by parallel processing of avoidance and palatability.

RevDate: 2020-03-09
CmpDate: 2020-03-09

Tanaka DH, Li S, Mukae S, et al (2019)

Genetic Access to Gustatory Disgust-Associated Neurons in the Interstitial Nucleus of the Posterior Limb of the Anterior Commissure in Male Mice.

Neuroscience, 413:45-63.

Orofacial and somatic disgust reactions are observed in rats following intraoral infusion of not only bitter quinine (innate disgust) but also sweet saccharin previously paired with illness (learned disgust). It remains unclear, however, whether these innate and learned disgust reactions share a common neural basis and which brain regions, if any, host it. In addition, there is no established method to genetically access neurons whose firing is associated with disgust (disgust-associated neurons). Here, we examined the expression of cFos and Arc, two markers of neuronal activity, in the interstitial nucleus of the posterior limb of the anterior commissure (IPAC) of male mice that showed innate disgust and mice that showed learned disgust. Furthermore, we used a targeted recombination in active populations (TRAP) method to genetically label the disgust-associated neurons in the IPAC with YFP. We found a significant increase of both cFos-positive neurons and Arc-positive neurons in the IPAC of mice that showed innate disgust and mice that showed learned disgust. In addition, TRAP following quinine infusion (Quinine-TRAP) resulted in significantly more YFP-positive neurons in the IPAC, compared to TRAP following water infusion. A significant number of the YFP-positive neurons following Quinine-TRAP were co-labeled with Arc following the second quinine infusion, confirming that Quinine-TRAP preferentially labeled quinine-activated neurons in the IPAC. Our results suggest that the IPAC activity is associated with both innate and learned disgust and that disgust-associated neurons in the IPAC are genetically accessible by TRAP.

RevDate: 2020-03-09
CmpDate: 2020-02-24

Schier LA, Hyde KM, AC Spector (2019)

Conditioned taste aversion versus avoidance: A re-examination of the separate processes hypothesis.

PloS one, 14(6):e0217458.

Rats not only avoid ingesting a substance associated with LiCl toxicosis, but they display rejection reflexes (e.g., gapes) to its taste; this latter response is thought to reflect disgust or taste aversion. Prior work has shown that rats also avoid consuming foods/fluids associated with other adverse gastrointestinal (GI) effects like lactose indigestion but without the concomitant change in oromotor responses (taste reactivity; TR) indicative of aversion. Because of interpretive limitations of the methods used in those studies, we revisited the taste aversion-avoidance distinction with a design that minimized non-treatment differences among groups. Effects on intake and preference (Experiments 1a, 1b, and 2), as well as consummatory (TR, Experiment 1a and 1b) and appetitive (Progressive Ratio, Experiment 2) behaviors to the taste stimulus were assessed after training. In both experiments, rats were trained to associate 0.2% saccharin (CS) with intraduodenal infusions of LiCl, Lactose, or NaCl control. Rats trained with 18% lactose, 0.3 and 1.5 mEq/kg dose of LiCl subsequently avoided the taste CS in post-training single-bottle intake tests and two-bottle choice tests. However, only those trained with 1.5 mEq/kg LiCl displayed post-conditioning increases in taste CS-elicited aversive TR (Experiment 1a and 1b). This dose of LiCl also led to reductions in breakpoint for saccharin. The fact that conditioned avoidance is not always accompanied by changes in other common appetitive and/or consummatory indices of ingestive motivation further supports a functional dissociation between these processes, and highlights the intricacies of visceral influences on taste-guided ingestive motivation.

RevDate: 2020-03-09
CmpDate: 2020-02-25

Devineni AV, Sun B, Zhukovskaya A, et al (2019)

Acetic acid activates distinct taste pathways in Drosophila to elicit opposing, state-dependent feeding responses.

eLife, 8:.

Taste circuits are genetically determined to elicit an innate appetitive or aversive response, ensuring that animals consume nutritious foods and avoid the ingestion of toxins. We have examined the response of Drosophila melanogaster to acetic acid, a tastant that can be a metabolic resource but can also be toxic to the fly. Our data reveal that flies accommodate these conflicting attributes of acetic acid by virtue of a hunger-dependent switch in their behavioral response to this stimulus. Fed flies show taste aversion to acetic acid, whereas starved flies show a robust appetitive response. These opposing responses are mediated by two different classes of taste neurons, the sugar- and bitter-sensing neurons. Hunger shifts the behavioral response from aversion to attraction by enhancing the appetitive sugar pathway as well as suppressing the aversive bitter pathway. Thus a single tastant can drive opposing behaviors by activating distinct taste pathways modulated by internal state.

RevDate: 2020-03-11
CmpDate: 2020-03-11

González-Sánchez H, Tovar-Díaz J, Morin JP, et al (2019)

NMDA receptor and nitric oxide synthase activity in the central amygdala is involved in the acquisition and consolidation of conditioned odor aversion.

Neuroscience letters, 707:134327.

Rats readily learn to avoid a tasteless odorized solution if they experience visceral malaise after consuming it. This phenomenon is referred to as conditioned odor aversion (COA). Several studies have shown that COA depends on the functional integrity of the amygdala, with most studies focusing on the basolateral nucleus. On the other hand, the role of the central amygdala (CeA) which is known to be involved in the consolidation of conditioned taste aversion (CTA) remains to be established. To address this issue, we evaluated the effect of inhibiting NMDA receptor activity in this structure on COA memory formation. Intra-CeA infusions of non-competitive NMDA receptor inhibitor MK-801 prevented memory formation both when administered before and up to 15 min after COA conditioning, while no effect of this drug was observed when given before long-term memory test. We next evaluated the role of one of the main downstream effectors of brain NMDA receptor signaling, nitric oxide synthase (NOS), known to play a key role in a wide variety learning tasks including some types of olfactory conditioning. Similar results were obtained with inhibition of either NOS or neuron-specific NOS; which proved to be required both during and after COA training, though for a shorter time span than NMDA receptors. Also, neither isoform showed to be required to memory retrieval. These results suggest that the US signaling during acquisition and the initial consolidation step of COA depends on glutamate-NO system activation in the CeA.

RevDate: 2020-11-26
CmpDate: 2020-05-27

Dannenhoffer CA, LP Spear (2019)

Excitatory/inhibitory balance across ontogeny contributes to age-specific behavioral outcomes of ethanol-like challenge in conditioned taste aversion.

Developmental psychobiology, 61(8):1157-1167.

Adolescent-typical sensitivities to ethanol (EtOH) are characterized in part by reduced sensitivity to EtOH's aversive effects. Rodent studies have shown that adolescents are less sensitive than adults to aversive properties of EtOH in a conditioned taste aversion (CTA) paradigm. To the extent that EtOH exerts antagonist-like actions upon glutamate receptors and/or agonist-like actions upon γ-aminobutyric acid (GABA) receptors, age differences in excitatory/inhibitory balance may regulate age-specific EtOH sensitivities, such as attenuated sensitivity of adolescents to EtOH aversion. In our experiments, adolescent and adult Sprague-Dawley rats were tested for CTA following challenge with one of the following pharmacological agents: glutamatergic AMPA1 receptor antagonist NBQX, glutamatergic N-methyl-d-aspartate NR2B receptor antagonist ifenprodil, and extrasynaptic GABAA receptor agonist THIP to determine whether these induced age-specific aversive sensitivities like those seen with EtOH. NBQX administration did not induce CTA. The highest dose of extrasynaptic GABAA agonist THIP induced CTA in adolescents but not adults, an opposite ontogenetic profile as seen following EtOH. Ifenprodil exerted an age-specific pattern of CTA similar to that seen with EtOH in males, with adolescents being insensitive to ifenprodil's aversive effects relative to adults. Thus, only antagonism of NR2B receptors in male rats mimicked age-specific sensitivities to the aversive effects of EtOH.

RevDate: 2020-06-23
CmpDate: 2020-06-23

Grau-Perales AB, Gómez-Chacón B, M Gallo (2019)

Differential activity pattern of c-Fos in the nucleus accumbens between adult and aged rats during flavor recognition memory.

Behavioural brain research, 371:111935.

Previous studies have addressed the role of the nucleus accumbens core (NAcbC) and shell (NAcbSh) in taste aversion learning and in the processing of taste palatability which is affected by aging. However, little is known about its implication in safe taste memory and the aging impact. To explore the role of the NAcb in flavor neophobia and its attenuation during aging, we applied c-Fos immunohistochemistry as an index of neural activity of the NAcbC and NAcbSh. Twenty one adult (5-month-old) and 24 aged (24-month-old) male Wistar rats were exposed to a 3% cider vinegar solution for 1, 2 or 6 consecutive days (n = 7 adult and n = 8 aged rats per group). Aged rats exhibited slower attenuation of flavor neophobia than adult rats. Adult rats showed increased NAcbSh c-Fos activity on day 2 compared to days 1 and 6, while this increase was delayed to day 6 in aged rats. There were no differences in the number of NAcbC c-Fos positive cells. This suggests that changes in the activity of neural circuits of palatability processing during normal aging could contribute to the slower attenuation of flavor neophobia in aged rats.

RevDate: 2020-09-29

Totani Y, Aonuma H, Oike A, et al (2019)

Monoamines, Insulin and the Roles They Play in Associative Learning in Pond Snails.

Frontiers in behavioral neuroscience, 13:65.

Molluscan gastropods have long been used for studying the cellular and molecular mechanisms underlying learning and memory. One such gastropod, the pond snail Lymnaea stagnalis, exhibits long-term memory (LTM) following both classical and operant conditioning. Using Lymnaea, we have successfully elucidated cellular mechanisms of learning and memory utilizing an aversive classical conditioning procedure, conditioned taste aversion (CTA). Here, we present the behavioral changes following CTA training and show that the memory score depends on the duration of food deprivation. Then, we describe the relationship between the memory scores and the monoamine contents of the central nervous system (CNS). A comparison of learning capability in two different strains of Lymnaea, as well as the filial 1 (F1) cross from the two strains, presents how the memory scores are correlated in these populations with monoamine contents. Overall, when the memory scores are better, the monoamine contents of the CNS are lower. We also found that as the insulin content of the CNS decreases so does the monoamine contents which are correlated with higher memory scores. The present review deepens the relationship between monoamine and insulin contents with the memory score.

RevDate: 2020-07-15
CmpDate: 2020-01-13

Williams RSB, PLR Andrews (2019)

Advice on avoiding the Valley of Death: insights from a 3Rs model of aversive and emetic compound identification.

ALTEX, 36(3):466-469.

RevDate: 2020-06-01
CmpDate: 2019-12-23

Ratner C, He Z, Grunddal KV, et al (2019)

Long-Acting Neurotensin Synergizes With Liraglutide to Reverse Obesity Through a Melanocortin-Dependent Pathway.

Diabetes, 68(6):1329-1340.

Neurotensin (NT), a gut hormone and neuropeptide, increases in circulation after bariatric surgery in rodents and humans and inhibits food intake in mice. However, its potential to treat obesity and the subsequent metabolic dysfunctions have been difficult to assess owing to its short half-life in vivo. Here, we demonstrate that a long-acting, pegylated analog of the NT peptide (P-NT) reduces food intake, body weight, and adiposity in diet-induced obese mice when administered once daily for 6 days. Strikingly, when P-NT was combined with the glucagon-like peptide 1 mimetic liraglutide, the two peptides synergized to reduce food intake and body weight relative to each monotherapy, without inducing a taste aversion. Further, P-NT and liraglutide coadministration improved glycemia and reduced steatohepatitis. Finally, we show that the melanocortin pathway is central for P-NT-induced anorexia and necessary for the full synergistic effect of P-NT and liraglutide combination therapy. Overall, our data suggest that P-NT and liraglutide combination therapy could be an enhanced treatment for obesity with improved tolerability compared with liraglutide monotherapy.

RevDate: 2020-03-10
CmpDate: 2020-03-10

Keeley A, Teo M, Ali Z, et al (2019)

In Vitro Dissolution Model Can Predict the in Vivo Taste Masking Performance of Coated Multiparticulates.

Molecular pharmaceutics, 16(5):2095-2105.

The majority of active pharmaceutical ingredients (APIs) are bitter. Therefore, compliance can be a problem where adequate taste masking has not been achieved; this is most problematic in pediatrics. Taste masking is thus a key stage during pharmaceutical development with an array of strategies available to the formulation scientist. Solid oral dosage forms can be taste-masked quite simply by polymer coating, which prevents drug release in the mouth, without unwantedly impairing drug release further down the gastrointestinal tract. At the early stages of pharmaceutical development, an in vitro method for the assessment of taste masking is necessary given the lack of toxicological data preventing the use of human taste panels. Currently, there is no such tool allowing prediction of taste masking efficiency. In this study, drug dissolution in the context of aversive taste thresholds was proposed as a means to bridge this knowledge gap. Thus, a biorelevant buccal dissolution test was developed in which previously determined taste thresholds in vivo were used to evaluate taste masking efficiency: if drug release exceeded said thresholds, the formulation was deemed to be poorly taste-masked, and vice versa. This novel dissolution test was compared to the USP I (basket) dissolution test, and the biopharmaceutical implications of taste masking were also assessed by performing USP I (basket) dissolution testing in simulated gastric fluid (SGF). Chlorphenamine maleate, a model bitter BCS class 1 API, was layered onto sugar spheres and taste-masked using polymer coatings. An array of coating technologies were employed and assessed single blinded: two pH-independent water-insoluble coatings (Surelease:Opadry at 8, 12, and 16% weight gain and Opadry EC at 4, 6, and 8% weight gain) and a pH-dependent water-insoluble reverse-enteric coating (developmental fully formulated system based on Kollicoat Smartseal 100P at 10% weight gain). Both the biorelevant buccal and the USP I dissolution tests were capable of discriminating between both type and level of coating used. However, only the buccal dissolution test was able to provide absolute quantification of the level of taste masking achieved in the context of previously determined taste thresholds, while the USP I test merely provided a relative comparison between the different technologies assessed. When the release data from the buccal test were assessed in parallel to that in SGF, it was possible to predict in vitro optimized taste masking without compromising bioavailability. The fully formulated system based on Smartseal 100P was identified as the most effective coating and Surelease:Opadry the least effective. The developed methodology provides true insight for the formulator, enabling more informed patient-centric formulation decisions, better taste masking, and ultimately more effective medicines.

RevDate: 2020-08-01
CmpDate: 2020-06-12

Saalfield J, L Spear (2019)

Fos activation patterns related to acute ethanol and conditioned taste aversion in adolescent and adult rats.

Alcohol (Fayetteville, N.Y.), 78:57-68.

Studies in rats have revealed marked age differences in sensitivity to the aversive properties of ethanol, with a developmental insensitivity to ethanol aversion that is most pronounced during pre- and early adolescence, declining thereafter to reach the enhanced aversive sensitivity of adults. The adolescent brain undergoes significant transitions throughout adolescence, including in regions linked with drug reward and aversion; however, it is unknown how ontogenetic changes within this reward/aversion circuitry contribute to developmental differences in aversive sensitivity. The current study examined early adolescent (postnatal day [P]28-30) and adult (P72-74) Sprague-Dawley male rats for conditioned taste aversion (CTA) after doses of 0, 1.0, or 2.5 g/kg ethanol, and patterns of neuronal activation in response to ethanol using Fos-like immunohistochemistry (Fos+) to uncover regions where age differences in activation are associated with ethanol aversion. An adolescent-specific ethanol-induced increase in Fos+ staining was seen within the nucleus accumbens shell and core. An age difference was also noted within the Edinger-Westphal nucleus (EW) following administration of the lower dose of ethanol, with 1 g/kg ethanol producing CTA in adults but not in adolescents and inducing a greater EW Fos response in adults than adolescents. Regression analysis revealed that greater numbers of Fos+ neurons within the EW and insula (Ins) were related to lower consumption of the conditioned stimulus (CS) on test day (reflecting greater CTA). Some regionally specific age differences in Fos+ were noted under baseline conditions, with adolescents displaying fewer Fos+ neurons than adults within the prelimbic (PrL) cortex, but more than adults in the bed nucleus of the stria terminalis (BNST). In the BNST (but not PrL), ethanol-induced increases in Fos-immunoreactivity (IR) were evident at both ages. Increased ethanol-induced activity within critical appetitive brain regions (NAc core and shell) supports a role for greater reward-related activation during adolescence, possibly along with attenuated responsiveness to ethanol in EW and Ins in the age-typical resistance of adolescents to the aversive properties of ethanol.

RevDate: 2020-05-05
CmpDate: 2020-05-05

Pohjanvirta R, S Mahiout (2019)

Aryl hydrocarbon receptor is indispensable for β-naphthoflavone-induced novel food avoidance and may be involved in LiCl-triggered conditioned taste aversion in rats.

Physiology & behavior, 204:58-64.

Previous studies have shown that several aryl hydrocarbon receptor (AHR) agonists, including β-naphthoflavone (BNF), elicit avoidance of novel food items in rodents, with this behavioral response displaying a similar dose-response to hepatic induction of CYP1A1. The avoidance has been found to bear substantial similarity to conditioned taste avoidance/aversion (CTA). The present study set out to confirm the indispensability of AHR in the avoidance response, to verify whether vagal afferent fibers are involved in it, and to see if AHR signaling might interfere with the effect of the classic trigger of CTA, LiCl. To this end, globally AHR deficient (AHRKO) or vagotomized wildtype rats were treated by gavage with 60 mg/kg BNF or ip with 0.15 M LiCl (4 ml/kg), and presented with chocolate which was either novel or familiar to them. Both the avoidance response and Cyp1a1 induction were missing in AHRKO rats. In contrast, Ahr+/- rats exhibited them in full, save for a single outlier. Total subdiaphragmatic vagotomy failed to interfere with the avoidance of novel or familiar chocolate or induction of Cyp1a1. After LiCl administration, male AHRKO rats showed a significantly mitigated suppression of chocolate consumption compared with wildtype animals (~60% vs. ~10% of control chocolate intake, respectively). A similar tendency was seen in females, but they were less responsive to LiCl. These findings corroborate AHR as a prerequisite of the BNF-induced novel food avoidance, prove vagal afferents unlikely mediators of this response, and imply an unforeseen involvement of AHR signaling in the thoroughly-characterized CTA instigated by LiCl.

RevDate: 2019-10-07
CmpDate: 2019-10-07

Katzman DK, Norris ML, N Zucker (2019)

Avoidant restrictive food intake disorder: First do no harm.

The International journal of eating disorders, 52(4):459-461.

OBJECTIVE: This opinion piece offers some considerations, both medical and psychological, for the use of nasogastric tube (NGT) feedings in the treatment of avoidant restrictive food intake disorder (ARFID) in children and adolescents.

METHOD: Although there is empirical support for the use of NGT feedings in the treatment of anorexia nervosa, this evidence base does not exist for the treatment of ARFID. As such, there is need to delineate pragmatic considerations in the use of this procedure.

RESULTS: Issues of medical necessity notwithstanding, we advise that the use of this procedure be considered more cautiously due to the oral sensitivities inherent in many individuals with ARFID and the potential psychological consequences. These sensitivities may make the experience of NGT feedings particularly aversive, with the potential of creating iatrogenic conditioned food aversions.

DISCUSSION: This article encourages clinicians to give careful thought and attention when considering NGT feedings in children and adolescents with ARFID.

RevDate: 2021-01-09
CmpDate: 2020-05-11

Patel S, Alvarez-Guaita A, Melvin A, et al (2019)

GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

Cell metabolism, 29(3):707-718.e8.

GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.

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Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

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