From fringe to mainstream: The Garcia effect.

The rejection of research results is sometimes thought to be justified in cases of individuals embracing fringe ideas that depart significantly from prevailing orthodoxy, or in cases of individuals who lack appropriate expertise or credentials. The case of John Garcia exhibits both of these dimensions, and illustrates that such rejection can delay scientific advancements. Garcia's work decisively challenged what was the orthodoxy in psychology in the midcentury: behaviorism. Behaviorist learning theorists suffered from theory-entrenchment insofar as they failed to acknowledge Garcia's anomalous research findings that ran counter to their theoretical expectations. The case study also illustrates that theories on the margins can become embraced as a result of advancements in adjacent research fields. Studying how Garcia's work moved from fringe to mainstream results in lessons for the philosophy of science and epistemology more generally. Only when we see the mechanisms of exclusion at work can we understand how science and other knowledge production systems can inadvertently act counterproductively via gatekeeping practices that filter out unorthodox points of view.

Distinct Progressions of Neuronal Activity Changes Underlie the Formation and Consolidation of a Gustatory Associative Memory.

Acquiring new memories is a multistage process. Numerous studies have convincingly demonstrated that initially acquired memories are labile and are stabilized only by later consolidation processes. These multiple phases of memory formation are known to involve modification of both cellular excitability and synaptic connectivity, which in turn change neuronal activity at both the single neuron and ensemble levels. However, the specific mapping between the known phases of memory and the changes in neuronal activity at different organizational levels-the single-neuron, population representations, and ensemble-state dynamics-remains unknown. Here we address this issue in the context of conditioned taste aversion learning by continuously tracking gustatory cortex neuronal taste responses in alert male and female rats during the 24 h following a taste-malaise pairing. We found that the progression of activity changes depends on the neuronal organizational level: whereas the population response changed continuously, the population mean response amplitude and the number of taste-responsive neurons only increased during the acquisition and consolidation phases. In addition, the known quickening of the ensemble-state dynamics associated with the faster rejection of harmful foods appeared only after consolidation. Overall, these results demonstrate how complex dynamics in the different representational levels of cortical activity underlie the formation and stabilization of memory within the cortex.SIGNIFICANCE STATEMENT Memory formation is a multiphased process; early acquired memories are labile and consolidate to their stable forms over hours and days. The progression of memory is assumed to be supported by changes in neuronal activity, but the mapping between memory phases and neuronal activity changes remains elusive. Here we tracked cortical neuronal activity over 24 h as rats acquired and consolidated a taste-malaise association memory, and found specific differences between the progression at the single-neuron and populations levels. These results demonstrate how balanced changes on the single-neuron level lead to changes in the network-level representation and dynamics required for the stabilization of memories.

Behavioral and neural responses to high-strength magnetic fields are reduced in otolith mutant mice.

Static high magnetic fields (MFs) interact with the vestibular system of humans and rodents. In rats and mice, exposure to MFs causes perturbations such as head movements, circular locomotion, suppressed rearing, nystagmus, and conditioned taste aversion acquisition. To test the role of otoconia, two mutant mouse models were examined, head-tilt Nox3het (het) and tilted Otop1 (tlt), with mutations, respectively, in Nox3, encoding the NADPH oxidase 3 enzyme, and Otop1, encoding the otopetrin 1 proton channel, which are normally expressed in the otolith organs, and are critical for otoconia formation. Consequently, both mutants show a near complete loss of otoconia in the utricle and saccule, and are nonresponsive to linear acceleration. Mice were exposed to a 14.1 Tesla MF for 30 min. After exposure, locomotor activity, conditioned taste aversion and c-Fos (in het) were assessed. Wild-type mice exposed to the MF showed suppressed rearing, increased latency to rear, locomotor circling, and c-Fos in brainstem nuclei related to vestibular processing (prepositus, spinal vestibular, and supragenual nuclei). Mutant het mice showed no response to the magnet and were similar to sham animals in all assays. Unlike het, tlt mutants exposed to the MF showed significant locomotor circling and suppressed rearing compared with sham controls, although they failed to acquire a taste aversion. The residual responsiveness of tlt versus het mice might reflect a greater semicircular deficit in het mice. These results demonstrate the necessity of the otoconia for the full effect of exposure to high MFs, but also suggest a semicircular contribution.

Taste aversion learning in the snail Cornu aspersum.

The present study was conducted to provide evidence of conditioned taste aversion learning (CTA) in the snail Cornu aspersum, using quinidine as the aversive stimulus in a procedure of Pavlovian Conditioning of Tentacle Lowering. Subjects were split into two groups: paired and unpaired. During the devaluation phase, subjects from the "paired group" received the US followed by the quinidine exposure, while subjects from the "unpaired group" received the quinidine and, 30 min later, the US. Subjects which had received the US paired with the quinidine showed a decrease of the conditioned response (CR), in contrast to subjects which had received the quinidine and the US unpaired. These results provide a useful CTA procedure in terrestrial snails. The implication of the results for learning and the physiological correlates is discussed.

Expression Level Changes in Serotonin Transporter are Associated with Food Deprivation in the Pond Snail Lymnaea stagnalis.

In the pond snail Lymnaea stagnalis, serotonin (5-HT) plays an important role in feeding behavior and its associated learning (e.g., conditioned taste aversion: CTA). The 5-HT content in the central nervous system (CNS) fluctuates with changes in the nutritional status, but it is also expected to be influenced by changes in the serotonin transporter (SERT) expression level. In the present study, we identified SERT in Lymnaea and observed its localization in 5-HTergic neurons, including the cerebral giant cells (CGCs) in the cerebral ganglia and the pedal A cluster neurons and right and left pedal dorsal 1 neurons in the pedal ganglia by in situ hybridization. Real-time PCR revealed that the SERT mRNA expression level was lower under severe food deprivation than under mild food deprivation in the whole CNS as well as in a single CGC. These results inversely correlated with previous data that the 5-HT content in the CNS was higher in the severely food-deprived state than in the mildly food-deprived state. Furthermore, in single CGCs, we observed that the 5-HT level was significantly increased in the severely food-deprived state compared with the mildly food-deprived state. Our present findings suggest that changes in the SERT expression level associated with food deprivation may affect 5-HT signaling, probably contributing to learning and memory mechanisms in Lymnaea.

CNS serotonin content mediating food deprivation-enhanced learning is regulated by hemolymph tryptophan concentration and autophagic flux in the pond snail.

Nutritional status affects cognitive function in many types of organisms. In the pond snail Lymnaea stagnalis, 1 day of food deprivation enhances taste aversion learning ability by decreasing the serotonin (5-hydroxytryptamin; 5-HT) content in the central nervous system (CNS). On the other hand, after 5 days of food deprivation, learning ability and the CNS 5-HT concentration return to basal levels. How food deprivation leads to alterations of 5-HT levels in the CNS, however, is unknown. Here, we measured the concentration of the 5-HT precursor tryptophan in the hemolymph and CNS, and demonstrated that the CNS tryptophan concentration was higher in 5-day food-deprived snails than in non-food-deprived or 1-day food-deprived snails, whereas the hemolymph tryptophan concentration was not affected by the duration of food deprivation. This finding suggests the existence of a mediator of the CNS tryptophan concentration independent of food deprivation. To identify the mediator, we investigated autophagic flux in the CNS under different food deprivation conditions. We found that autophagic flux was significantly upregulated by inhibition of the tropomyosin receptor kinase (Trk)-Akt-mechanistic target of rapamycin complex 1 (MTORC1) pathway in the CNS of 5-day food-deprived snails. Moreover, when autophagy was inhibited, the CNS 5-HT content was significantly downregulated in 5-day food-deprived snails. Our results suggest that the hemolymph tryptophan concentration and autophagic flux in the CNS cooperatively regulate learning ability affected by different durations of food deprivation. This mechanism may underlie the selection of behaviors appropriate for animal survival depending on the degree of nutrition.

Virus-mediated GHS-R1a expression in the basolateral amygdala blocks extinction of conditioned taste aversion memory in rats.

Ghrelin is an orexigenic gastric hormone that promotes feeding behaviors and regulating energy homeostasis in both humans and rodents. Our previous studies have shown that ghrelin, when locally infused into the basolateral amygdala (BLA), blocks both acquisition and extinction of conditioned taste aversion (CTA) memory in rats. In this study, we further investigated the effect of virus-mediated overexpression of ghrelin receptor growth hormone secretagogue receptor 1a (GHS-R1a) in BLA pyramidal neurons on CTA memory processes. We found that upregulation of GHS-R1a expression in BLA pyramidal neurons repressed CTA extinction while it had no effect on CTA acquisition. In addition, we reported that local infusion of the endogenous GHS-R1a antagonist, liver-expressed antimicrobial peptide 2 (LEAP2), in the BLA abolished the inhibitory effect of increased GHS-R1a on CTA memory extinction. Those findings provide new supportive evidence that ghrelin/GHS-R1a signaling in the BLA circuit shapes emotional memory processes.

Decreased taste sensitivity to sucrose in dopamine D3 receptor mutant mice.

Dopamine plays a key role in food rewards and sweet-taste stimulation. We examined the basis for behavioral responses to sweet taste in dopamine D3 receptor-deficient (D3-/-) mice by determining whether the absence of D3 receptors affects the sensitivity to dilute sucrose solutions. In experiment 1, we measured the intensity generalization threshold of conditioned taste aversion (CTA) to a 0.2 M sucrose solution. Results showed that the generalization thresholds were 0.025-0.05 M in D3-/- mice and 0.0025-0.005 M in wild-type (WT) mice. In experiment 2, we found that D3-/- and WT mice had similar capabilities to form and extinguish CTAs. Since the intensity generalization threshold is mainly due to a combination of sweet-taste sensitivity and the robust nature of CTA formation, the results showed that taste sensitivity to sucrose in D3-/- mice was lower than that in WT mice. In experiment 3, to test whether the peripheral sensory signaling may also be affected by the disruption of the dopamine D3 receptors, the mRNA expression levels of sweet-taste-related proteins in taste buds of D3-/- mice were determined. The T1R1 and BDNF mRNA expression levels in D3-/- mice were higher than the controls, whereas T1R2, T1R3, α-gustducin, and TRPM5 mRNA were similar. These findings suggest that disruption of dopamine D3 receptor-mediated signaling decreases the sweet-taste sensitivity and alters the mRNA expression levels of some taste-related molecules.

Ghrelin infusion into the basolateral amygdala suppresses CTA memory formation in rats via the PI3K/Akt/mTOR and PLC/PKC signaling pathways.

Ghrelin is a circulating orexigenic hormone that promotes feeding behavior and regulates metabolism in humans and rodents. We previously reported that local infusion of ghrelin into the basolateral amygdala (BLA) blocked memory acquisition for conditioned taste aversion (CTA) by activating growth hormone secretagogue receptor 1a. In this study, we further explored the underlying mechanism and signaling pathways mediating ghrelin modulation of CTA memory in rats. Pharmacological agents targeting distinct signaling pathways were infused into the BLA during conditioning. We showed that preadministration of the PI3K inhibitor LY294002 abolished the repressive effect of ghrelin on CTA memory. Moreover, LY294002 pretreatment prevented ghrelin from inhibiting Arc and zif268 mRNA expression in the BLA triggered by CTA memory retrieval. Preadministration of rapamycin eliminated the repressive effect of ghrelin, while Gsk3 inhibitors failed to mimic ghrelin's effect. In addition, PLC and PKC inhibitors microinfused in the BLA blocked ghrelin's repression of CTA acquisition. These results demonstrate that ghrelin signaling in the BLA shapes CTA memory via the PI3K/Akt/mTOR and PLC/PKC pathways. We conducted in vivo multichannel recordings from mouse BLA neurons and found that microinjection of ghrelin (20 µM) suppressed intrinsic excitability. By means of whole-cell recordings from rat brain slices, we showed that bath application of ghrelin (200 nM) had no effect on basal synaptic transmission or synaptic plasticity of BLA pyramidal neurons. Together, this study reveals the mechanism underlying ghrelin-induced interference with CTA memory acquisition in rats, i.e., suppression of intrinsic excitability of BLA principal neurons via the PI3K/Akt/mTOR and PLC/PKC pathways.

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

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 ß-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.

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

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.

Effects of learning and adaptation on population viability.

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.

La adaptación cultural es un medio mediante el cual los conservacionistas pueden ayudar a las poblaciones a adaptarse a las amenazas. Un comportamiento aprendido puede proteger a un individuo de las amenazas y este comportamiento puede transmitirse horizontalmente (dentro de las generaciones) y verticalmente (entre generaciones), lo que otorga rápidamente una protección a nivel poblacional. Aunque esto es posible en teoría, aún no está claro si dichas manipulaciones funcionan dentro de un escenario de conservación; cuáles son las condiciones requeridas para que funcionen las manipulaciones; y cómo pueden afectar el proceso evolutivo. Examinamos modelos en los cuales una población puede adaptarse tanto con mecanismos genéticos como culturales. Nuestro trabajo estuvo motivado por la invasión de sapos altamente tóxicos (Rhinella marina) en todo el norte de Australia y las declinaciones resultantes de cuoles norteños (Dasyurus hallucatus), los cuales atacan y mueren envenenados por los sapos tóxicos. Analizamos si una estrategia de manejo novedoso en la cual los cuoles silvestres son entrenados para evitar a los sapos puede reducir la probabilidad de extinción. Usamos un modelo de simulación diseñado alrededor de la historia de vida de los cuoles. Dentro de las simulaciones, se entrenó a cuoles individuales y una característica en continua evolución determinó la tendencia innata para atacar a los sapos. Aplicamos este modelo en un escenario de viabilidad poblacional. La estrategia redujo la probabilidad de extinción sólo cuando la heredabilidad de la aversión innata fue baja (<20%) y cuando las madres entrenadas entrenaron a más del 70% de sus crías para evitar a los sapos. Cuando ambas condiciones fueron cumplidas, la adaptación genética fue más lenta pero la adaptación cultural rápida mantuvo a la población vigente mientras se completaba la adaptación genética. Para ganar conocimiento sobre las dinámicas evolutivas (en las cuales vimos un pico transitorio en la adaptación cultural a lo largo del tiempo) también desarrollamos un modelo analítico simple de las dinámicas evolutivas. Este modelo mostró que la fuerza de la selección natural declinó conforme incrementó la tasa de transmisión cultural y que la adaptación procedió solamente cuando la tasa de transmisión cultural estuvo por debajo de un valor crítico determinado por los niveles relativos de protección otorgados por los mecanismos genéticos contra los mecanismos evolutivos. En conjunto, nuestros modelos mostraron que la adaptación cultural puede jugar un papel importante en la prevención de la extinción, pero las tasas de transmisión cultural necesitan ser altas para que esto ocurra.

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

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.

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

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.

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

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.

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

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.

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

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.

Avoidant restrictive food intake disorder: First do no harm.

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.

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

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.

Inhibiting gustatory thalamus or medial amygdala has opposing effects on taste neophobia.

Taste neophobia is a feeding system defense mechanism that limits consumption of an unknown, and therefore potentially dangerous, edible until the post-ingestive consequences are experienced. We found that transient pharmacological inhibition (induced with the GABA agonists baclofen and muscimol) of the gustatory thalamus (GT; Experiment 1), but not medial amygdala (MeA; Experiment 2), during exposure to a novel saccharin solution attenuated taste neophobia. In Experiment 3 we found that inhibition of MeA neurons (induced with the chemogenetic receptor hM4DGi) enhanced the expression of taste neophobia whereas excitation of MeA neurons (with hM3DGq) had no influence of taste neophobia. Overall, these results refine the temporal involvement of the GT in the occurrence of taste neophobia and support the hypothesis that neuronal excitation in the GT is necessary for taste neophobia. Conversely, we show that chemogenetically, but not pharmacologically, inhibiting MeA neurons is sufficient to exaggerate the expression of taste neophobia.