Taste memory formation: role of nucleus accumbens

When a novel taste has been associated with postingestive malaise, animals recognize this taste as aversive. This associative learning is known as conditioned taste aversion. However, when an animal consumes a novel taste and no aversive consequences follow, it becomes recognized as a safe signal, leading to an increase in its consumption in subsequent presentations. In this review, we will discuss the results related to the taste memory formation focusing particularly on the nucleus accumbens (NAcc). The NAcc keeps projections with amygdala, insular cortex, parabrachial nucleus, and nucleus of the solitary tract areas important for taste memory formation. We will review the evidence relating to how the NAcc could be involved in taste memory formation, due to its role in the taste memory trace formation and its role in the association of the conditioned stimulus-unconditioned stimulus, and finally the retrieval of taste memory. In this context, we will review the participation of the cholinergic, dopaminergic, and glutamatergic systems in the NAcc during taste memory formation.     

Molecular Signals into the Insular Cortex and Amygdala During Aversive Gustatory Memory Formation

In this paper, we will provide evidence of the putative molecular signals and biochemical events that mediate the formation of long-lasting gustatory memory trace. When an animal drinks a novel taste (the conditioned stimulus; CS) and it is later associated with malaise (unconditioned stimulus; US), the animal will reject it in the next presentation, developing a long-lasting taste aversion, i.e., the taste cue becomes an aversive signal, and this is referred to as conditioning taste aversion. Different evidence indicates that the novel stimulus (taste) induces a rapid and strong cortical acetylcholine activity that decreases when the stimulus becomes familiar after several presentations. Cholinergic activation via muscarinic receptors initiates a series of intracellular events leading to plastic changes that could be related to short- and/or long-term memory gustatory trace. Such plastic changes facilitate the incoming US signals carried out by, in part, the glutamate release induced by the US. Altogether, these events could produce the cellular changes related to the switch from safe to aversive taste memory trace. A proposed working model to explain the biochemical sequence of signals during taste memory formation will be discussed.     

Animal models of memory impairment.

Memory impairment in the elderly resembles a mild temporal lobe dysfunction. Alterations in the hippocampal formation are also a probable basis for cognitive deficits in some animal models of ageing. For example, aged rats are impaired in hippocampal-dependent tests of spatial memory. Recent studies have revealed considerable structural integrity in the aged hippocampus, even in aged rats with the most impaired spatial memory. In contrast, atrophy/loss of cholinergic neurons in the basal forebrain and deficiency in cholinergic transduction in hippocampus correlate with the severity of spatial memory impairment in aged rats. This evidence supports the longstanding view that age-related loss of memory has a cholinergic basis. In this context, it is somewhat surprising that the use of a selective cholinergic immunotoxin in young rats to further test this hypothesis has revealed normal spatial memory after removing septo-hippocampal cholinergic neurons. Young rats with immunotoxic lesions, however, have other behavioural impairments in tests of attentional processing. These lines of research have implications for understanding the neurobiological basis of memory deficits in ageing and for selecting an optimal behavioural setting in which to examine therapies aimed at restoring neurobiological function.     

Taste aversion learning and aging: a comparison with the effect of dorsal hippocampal lesions in rats

The relationship between hippocampal function and aging was explored in Wistar rats using taste aversion learning by comparing the performance of adult dorsal hippocampal lesioned and fifteen-month-old intact rats with that of adult intact rats. In experiment 1 the conditioned blocking phenomenon was absent in the hippocampal and the aging rats. Unlike the adult intact rats, the hippocampal and aging rats were not impaired in acquiring a learned aversion to a cider vinegar solution (3 %) presented as a serial compound with a previously conditioned saccharin solution (0.1 %). In experiment 2 both the hippocampal and the aging rats developed reduced aversions to a saline solution (0.5 %) followed by an i.p. injection of lithium chloride (0.15 M; 2 % b.w.) if the taste solution was previously preexposed without consequences. This latent inhibition effect was similar to that seen in intact adult rats. In both experiments, the aging rats exhibited enhanced conventional learned taste aversions. It is concluded that aging is not a unitary process but induces both hippocampal dependent and hippocampal independent complex changes in the functioning of the neural circuits, implementing taste aversion learning.     

Experimental evolution of olfactory memory in Drosophila melanogaster

In order to address the nature of genetic variation in learning performance, we investigated the response to classical olfactory conditioning in "high-learning" Drosophila melanogaster lines previously subject to selection for the ability to learn an association between the flavor of an oviposition medium and bitter taste. In a T-maze choice test, the seven high-learning lines were better at avoiding an odor previously associated with aversive mechanical shock than were five unselected "low-learning" lines originating from the same natural population. Thus, the evolved improvement in learning ability of high-learning lines generalized to another aversion learning task involving a different aversive stimulus (shock instead of bitter taste) and a different behavioral context than that used to impose selection. In this olfactory shock task, the high-learning lines showed improvements in the learning rate as well as in two forms of consolidated memory: anesthesia-resistant memory and long-term memory. Thus, genetic variation underlying the experimental evolution of learning performance in the high-learning lines affected several phases of memory formation in the course of olfactory aversive learning. However, the two forms of consolidated memory were negatively correlated among replicate high-learning lines, which is consistent with a recent hypothesis that these two forms of consolidated memory are antagonistic.     

Amyloid β and impairment in multiple memory systems in older transgenic APP TgCRND8 mice

The relationship between amyloid beta and cognitive dysfunction in mouse models of Alzheimer's disease has been evaluated predominantly with the spatial reference memory version of the water maze task. However, as Alzheimer's disease encompasses decline in multiple memory systems, it is important to also utilize non-spatial tasks to fully characterize the role of amyloid on behaviour in animal models. We used the TgCRND8 mouse model of Alzheimer's disease to evaluate the effect of amyloid on spatial reference memory, as well as on the non-spatial task of acquisition of conditioned taste aversion, and on the procedural task of swimming to a visible platform. We demonstrate that 8- to 12-month-old TgCRND8 mice are significantly impaired in all three tasks, and that the levels of soluble amyloid beta are significantly correlated with impairment in spatial reference memory, but not with impairment in conditioned taste aversion or swimming to a visible platform. Insoluble fractions of amyloid, which correspond closely to amyloid plaque burden in the brain, are not associated with any behavioural measure. Our study extends the characterization of the model to stages of advanced amyloid pathology and demonstrates that older TgCRND8 mice are impaired in multiple memory systems, including procedural tasks, which are spared at younger ages. The lack of association between amyloid plaques and memory decline supports clinical findings in Alzheimer's patients.     

Human emotion and memory: interactions of the amygdala and hippocampal complex

The amygdala and hippocampal complex, two medial temporal lobe structures, are linked to two independent memory systems, each with unique characteristic functions. In emotional situations, these two systems interact in subtle but important ways. Specifically, the amygdala can modulate both the encoding and the storage of hippocampal-dependent memories. The hippocampal complex, by forming episodic representations of the emotional significance and interpretation of events, can influence the amygdala response when emotional stimuli are encountered. Although these are independent memory systems, they act in concert when emotion meets memory.     

Rapamycin Reverses Status Epilepticus-Induced Memory Deficits and Dendritic Damage

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.     

Overshadowing of running-based taste aversion learning by another taste cue

Training rats with serial presentations of two taste solutions before confinement in an activity wheel (X → A → running) resulted in weak aversion to taste X, compared to a training procedure without the presentation of A. Demonstration of the overshadowing effect in the present study provides another parallel feature between running-based taste aversion learning and Pavlovian conditioning preparations including poison-based taste aversion learning. It also indirectly supports the claim that cue competition causes degraded contingency effect and cover-cue effect in rats’ running-based taste aversion (Nakajima, 2008).     

Cdk5 Contributes to Huntington’s Disease Learning and Memory Deficits via Modulation of Brain Region-Specific Substrates

Cognitive deficits are a major hallmark of Huntington’s disease (HD) with a great impact on the quality of patient’s life. Gaining a better understanding of the molecular mechanisms underlying learning and memory impairments in HD is, therefore, of critical importance. Cdk5 is a proline-directed Ser/Thr kinase involved in the regulation of synaptic plasticity and memory processes that has been associated with several neurodegenerative disorders. In this study, we aim to investigate the role of Cdk5 in learning and memory impairments in HD using a novel animal model that expresses mutant huntingtin (mHtt) and has genetically reduced Cdk5 levels. Genetic reduction of Cdk5 in mHtt knock-in mice attenuated both corticostriatal learning deficits as well as hippocampal-dependent memory decline. Moreover, the molecular mechanisms by which Cdk5 counteracts the mHtt-induced learning and memory impairments appeared to be differentially regulated in a brain region-specific manner. While the corticostriatal learning deficits are attenuated through compensatory regulation of NR2B surface levels, the rescue of hippocampal-dependent memory was likely due to restoration of hippocampal dendritic spine density along with an increase in Rac1 activity. This work identifies Cdk5 as a critical contributor to mHtt-induced learning and memory deficits. Furthermore, we show that the Cdk5 downstream targets involved in memory and learning decline differ depending on the brain region analyzed suggesting that distinct Cdk5 effectors could be involved in cognitive impairments in HD.     

Selective cholinergic depletion in medial septum leads to impaired long term potentiation and glutamatergic synaptic currents in the hippocampus

Cholinergic depletion in the medial septum (MS) is associated with impaired hippocampal-dependent learning and memory. Here we investigated whether long term potentiation (LTP) and synaptic currents, mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the CA1 hippocampal region, are affected following cholinergic lesions of the MS. Stereotaxic intra-medioseptal infusions of a selective immunotoxin, 192-saporin, against cholinergic neurons or sterile saline were made in adult rats. Four days after infusions, hippocampal slices were made and LTP, whole cell, and single channel (AMPA or NMDA receptor) currents were recorded. Results demonstrated impairment in the induction and expression of LTP in lesioned rats. Lesioned rats also showed decreases in synaptic currents from CA1 pyramidal cells and synaptosomal single channels of AMPA and NMDA receptors. Our results suggest that MS cholinergic afferents modulate LTP and glutamatergic currents in the CA1 region of the hippocampus, providing a potential synaptic mechanism for the learning and memory deficits observed in the rodent model of selective MS cholinergic lesioning.     

Lesions of the Lateral Habenula Increase Voluntary Ethanol Consumption and Operant Self-Administration,Block Yohimbine-Induced Reinstatement of Ethanol Seeking,and Attenuate Ethanol-Induced Conditioned Taste Aversion

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown. In the present study, we compared voluntary ethanol consumption and self-administration, yohimbine-induced reinstatement of ethanol seeking, and ethanol-induced conditioned taste aversion in rats with sham or LHb lesions. In rats given home cage access to 20% ethanol in an intermittent access two bottle choice paradigm, lesioned animals escalated their voluntary ethanol consumption more rapidly than sham-lesioned control animals and maintained higher stable rates of voluntary ethanol intake. Similarly, lesioned animals exhibited higher rates of responding for ethanol in operant self-administration sessions. In addition, LHb lesion blocked yohimbine-induced reinstatement of ethanol seeking after extinction. Finally, LHb lesion significantly attenuated an ethanol-induced conditioned taste aversion. Our results demonstrate an important role for the LHb in multiple facets of ethanol-directed behavior, and further suggest that the LHb may contribute to ethanol-directed behaviors by mediating learning driven by the aversive effects of the drug.     

Endogenous IL-1 in Cognitive Function and Anxiety: A Study in IL-1RI?/? Mice

Interleukin-1 (IL-1) is a key pro-inflammatory cytokine, produced predominantly by peripheral immune cells but also by glia and some neuronal populations within the brain. Its signalling is mediated via the binding of IL-1α or IL-1β to the interleukin-1 type one receptor (IL-1RI). IL-1 plays a key role in inflammation-induced sickness behaviour, resulting in depressed locomotor activity, decreased exploration, reduced food and water intake and acute cognitive deficits. Conversely, IL-1 has also been suggested to facilitate hippocampal-dependent learning and memory: IL-1RI^−/− mice have been reported to show deficits on tasks of visuospatial learning and memory. We sought to investigate whether there is a generalised hippocampal deficit in IL-1RI^−/− animals. Therefore, in the current study we compared wildtype (WT) mice to IL-1RI^−/− mice using a variety of hippocampal-dependent learning and memory tasks, as well as tests of anxiety and locomotor activity. We found no difference in performance of the IL-1RI^−/− mice compared to WT mice in a T-maze working memory task. In addition, the IL-1RI^−/− mice showed normal learning in various spatial reference memory tasks including the Y-maze and Morris mater maze, although there was a subtle deficit in choice behaviour in a spatial discrimination, beacon watermaze task. IL-1RI^−/− mice also showed normal memory for visuospatial context in the contextual fear conditioning paradigm. In the open field, IL-1RI^−/− mice showed a significant increase in distance travelled and rearing behaviour compared to the WT mice and in the elevated plus-maze spent more time in the open arms than did the WT animals. The data suggest that, contrary to prior studies, IL-1RI^−/− mice are not robustly impaired on hippocampal-dependent memory and learning but do display open field hyperactivity and decreased anxiety compared to WT mice. The results argue for a careful evaluation of the roles of endogenous IL-1 in hippocampal and limbic system function.     

Prenatal ethanol exposure persistently impairs NMDA receptor-dependent activation of extracellular signal-regulated kinase in the mouse dentate gyrus

The dentate gyrus (DG) is the central input region to the hippocampus and is known to play an important role in learning and memory. Previous studies have shown that prenatal alcohol is associated with hippocampal-dependent learning deficits and a decreased ability to elicit long-term potentiation (LTP) in the DG in adult animals. Given that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade by NMDA receptors is required for various forms of learning and memory, as well as LTP, in hippocampal regions, including the DG, we hypothesized that fetal alcohol-exposed adult animals would have deficits in hippocampal NMDA receptor-dependent ERK1/2 activation. We used immunoblotting and immunohistochemistry techniques to detect NMDA-stimulated ERK1/2 activation in acute hippocampal slices prepared from adult fetal alcohol-exposed mice. We present the first evidence linking prenatal alcohol exposure to deficits in NMDA receptor-dependent ERK1/2 activation specifically in the DG of adult offspring. This deficit may account for the LTP deficits previously observed in the DG, as well as the life-long cognitive deficits, associated with prenatal alcohol exposure.     

咸味觉厌恶模型大鼠鼓索神经对味觉刺激的电生理反应特性

目的:探索大鼠咸味觉厌恶建立后外周鼓索神经(CT)对咸味觉及其他味觉刺激的电生理反应特性的改变。方法:将14只SD成年雄性大鼠分为咸味觉厌恶模型组(CTA)和对照组(n=7/group)。实验第1日给予大鼠30min的0.1mol/LNaCl饮食,随后CTA组和对照组大鼠分别腹腔注射2ml0.15mol/LLiCl和同等量生理盐水。在第2、3和4日,测量两组大鼠每天30min内对NaCl和蒸馏水饮用量。于第4日行为学测试后,分别记录CTA组大鼠和对照组大鼠CT对口内给予系列浓度NaCl溶液、0.3mol/LNaCl与0.1mmol/L阿米洛利(一种舌上皮钠通道阻断剂)混合液和其他四种基本味觉刺激溶液的电生理反应。结果:与对照组相比,CTA组大鼠CT对系列浓度NaCl和其他4种基本味觉刺激的电生理反应特性没有发生明显变化(P>0.05);舌上皮钠通道阻断剂阿米洛利强烈抑制CTA大鼠对NaCl的反应(P<0.01)。结论:条件性咸味觉厌恶模型大鼠CT对各种味觉刺激的电生理反应特性没有发生明显改变。     

Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.     

Memory retention capacity using two different training methods,appetitive and aversive learning,in juvenile red sea bream Chrysophrys major

Memory retention based on appetitive and aversive learning was studied in juvenile red sea bream Chrysophrys major. The fish were individually trained via appetitive and aversive learning. In general, they retained appetitive memories for 30 days, but not for 60 days. Conversely, aversive memory endured for 1 day, but not for 3 days or longer. Analyses at the individual level revealed that some fish retained appetitive memories for 60 days, whereas others lost it within 3 days; this suggests considerable variability in memory retention capacity among individual fish. The memory duration for aversive learning was remarkably short, which should be considered when releasing trained fish into the wild for stock enhancement. Furthermore, the high inter-individual variability suggests that evaluating memory retention capacity through group experiments might lead to overestimation of fishes’ ability.     

The radish gene reveals a memory component with variable temporal properties

Memory phases, dependent on different neural and molecular mechanisms, strongly influence memory performance. Our understanding, however, of how memory phases interact is far from complete. In Drosophila, aversive olfactory learning is thought to progress from short-term through long-term memory phases. Another memory phase termed anesthesia resistant memory, dependent on the radish gene, influences memory hours after aversive olfactory learning. How does the radish-dependent phase influence memory performance in different tasks? It is found that the radish memory component does not scale with the stability of several memory traces, indicating a specific recruitment of this component to influence different memories, even within minutes of learning.     

Cellular and systems reconsolidation in the hippocampus

Cellular theories of memory consolidation posit that new memories require new protein synthesis in order to be stored. Systems consolidation theories posit that the hippocampus has a time-limited role in memory storage, after which the memory is independent of the hippocampus. Here, we show that intra-hippocampal infusions of the protein synthesis inhibitor anisomycin caused amnesia for a consolidated hippocampal-dependent contextual fear memory, but only if the memory was reactivated prior to infusion. The effect occurred even if reactivation was delayed for 45 days after training, a time when contextual memory is independent of the hippocampus. Indeed, reactivation of a hippocampus-independent memory caused the trace to again become hippocampus dependent, but only for 2 days rather than for weeks. Thus, hippocampal memories can undergo reconsolidation at both the cellular and systems levels.     

Extensive Lesions in Rat Insular Cortex Significantly Disrupt Taste Sensitivity to NaCl and KCl and Slow Salt Discrimination Learning

While studies of the gustatory cortex (GC) mostly focus on its role in taste aversion learning and memory, the necessity of GC for other fundamental taste-guided behaviors remains largely untested. Here, rats with either excitotoxic lesions targeting GC (n = 26) or sham lesions (n = 14) were assessed for postsurgical retention of a presurgically LiCl-induced conditioned taste aversion (CTA) to 0.1M sucrose using a brief-access taste generalization test in a gustometer. The same animals were then trained in a two-response operant taste detection task and psychophysically tested for their salt (NaCl or KCl) sensitivity. Next, the rats were trained and tested in a NaCl vs. KCl taste discrimination task with concentrations varied. Rats meeting our histological inclusion criterion had large lesions (resulting in a group averaging 80% damage to GC and involving surrounding regions) and showed impaired postsurgical expression of the presurgical CTA (LiCl-injected, n = 9), demonstrated rightward shifts in the NaCl (0.54 log₁₀ shift) and KCl (0.35 log₁₀ shift) psychometric functions, and displayed retarded salt discrimination acquisition (n = 18), but eventually learned and performed the discrimination comparable to sham-operated animals. Interestingly, the degree of deficit between tasks correlated only modestly, if at all, suggesting that idiosyncratic differences in insular cortex lesion topography were the root of the individual differences in the behavioral effects demonstrated here. This latter finding hints at some degree of interanimal variation in the functional topography of insular cortex. Overall, GC appears to be necessary to maintain normal taste sensitivity to NaCl and KCl and for salt discrimination learning. However, higher salt concentrations can be detected and discriminated by rats with extensive damage to GC suggesting that the other resources of the gustatory system are sufficient to maintain partial competence in these tasks, supporting the view that such basic sensory-discriminative taste functions involve distributed processes among central gustatory structures.