Neurobiology of Learning and Memory最新文献

The deleterious effects of sleep loss on sleep-dependent memory and emotional function have been documented in the current literature. Yet, the effects of insomnia-induced chronic sleep disturbance on emotional short-term memory have been scarcely investigated. Twenty-one participants with subclinical insomnia disorder (SID) and 20 healthy participants (healthy control, HC) performed a delayed recognition task of emotional faces, and event-related potentials (ERPs) involved in memory encoding, retention, and retrieval of faces across different emotional valences were assessed. Behavioral findings revealed that participants in the SID group had a larger response bias, being more likely to perceive negative faces as “old” faces presented in the retrieval phase than those in the HC group. ERP findings revealed that emotional faces in the SID vs. HC group induced significantly smaller P1 and late P3b and larger N170 amplitudes in the encoding phase and smaller negative slow wave (NSW) in the retention phase. In retrieval phase, the interaction between Sleep group and Valence were revealed for P1 and early P3b amplitudes, but no group differences were found after Bonferroni correction. These findings suggested that insomnia induced chronic sleep disturbance would influence performance on emotional working memory and induced processing phase specific regulation of neurophysiology in emotional working memory regardless of valence.

The Nociceptin/Orphanin FQ (N/OFQ) system has been shown to modulate various aspects of long-term memory. It is therefore important to study the effects on memory impairment by nociceptin receptor (NOP) agonists under preclinical development. In the present study, we investigated the effect of systemic injection of two small molecule selective NOP agonists, AT-202 and AT-524, in the object location memory task in male and female mice. Since high doses of NOP agonists have been shown to induce sedation, we first determined the sedative doses for the two compounds and found them to be higher in female than in male mice. We then observed that sub-sedative doses of NOP agonists administered before learning, induced memory impairment during a test session performed 24 h later. Again, female mice were less sensitive to the amnesic effects than males. On the contrary, in male mice, NOP agonists did not produce amnesia when they were injected after learning, suggesting that they do not affect the consolidation of object location memory. Finally, repeated administration of high doses of NOP agonists over 7 days did not impair long-term spatial memory. Together, our data show for the first time that NOP receptor agonists impair the acquisition of object location memory with sex-dependent potency but do not affect memory consolidation, and that repeated stimulation of the receptor does not compromise long-term episodic-like spatial memory.

Environmental enrichment (EE) is known to improve memory and cognition and modulate the impact of aversive stimuli in animals, promoting the development of resilience to stressful situations. Likewise, it is known that EE can modulate synaptic plasticity as is the case of long-term potentiation (LTP). These findings have been described initially in ex vivo preparations, suggesting that the effects of EE are the result of an early modification of the synaptic excitability and transmission. In this regard, it is known that metaplasticity refers to the persistent modification, by previous activity, in the ability to induce synaptic plasticity. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of LTP in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. In addition, we have shown that CTA extinction allows the induction but not the maintenance of IC-LTP of the Bla-IC pathway. Recently, we also showed that prior exposure to environmental enrichment for three weeks reduces the strength of CTA, restoring the brain-derived neurotrophic factor (BDNF) levels in the IC. The present study aimed to analyze the effects of brief exposure to an enriched environment on the strength of aversive memory, as well as on the in vivo IC-LTP. To do so, adult rats were exposed for seven days to an EE, either before CTA training or LTP induction in the Bla-IC pathway. Our results demonstrate that a seven-day exposure to an enriched environment attenuates the aversive response to a strong CTA and allows the induction but not the maintenance of LTP in the insular cortex. These findings provide evidence that metaplastic regulation in a neocortical region takes part in the mechanisms through which brief exposure to enriched environments attenuates an aversive response.

Early life stress (ELS), including experiences with abuse and neglect, are related to several negative health outcomes in adulthood. One area that has received attention is the increased rate of substance abuse disorder in individuals who had experienced ELS. Given the critical role habitual behavior in the development of substance abuse, ELS may affect the trajectory of neural development such that habitual responding is more dominant than in individuals who did not experience ELS. Here, we examine learning of a probabilistic classification task (the Weather Prediction Task) in healthy young adults who reported significant ELS and those that did not. This task can be learned in a declarative, model-based manner, or in a more habitual, stimulus-response manner. Participants learned to choose the outcome (sun or rain) that was probabilistically associated with each cue combination through reinforcement on each trial. After 100 trials, the probabilities were reversed, and we conceptualized habitual behavior as perseverating responses based on the old probabilities. We also collected information about subjective socio-economic status (sSES), anxiety, depression, and substance use from participants. Using multiple regression, we found that our measure of habitual responding was correlated with reported alcohol use, suggesting that our measure of habit has validity for health behaviors. Furthermore, we found that some forms of early life stress led to greater response perseverance after contingencies were reversed. Overall, the results suggest that childhood adversity may contribute to the development of habit.

Contextual fear conditioning is a form of Pavlovian learning during which an organism learns to fear previously neutral stimuli following their close temporal presentation with an aversive stimulus. In mouse models, freezing behavior is typically used to quantify learned fear. This dependent variable is the sum of multiple processes, including associative/configural learning, fear and anxiety, and general activity. To explore phenotypic constructs underlying contextual fear conditioning and correlated behaviors, as well as factors that may contribute to individual differences in learning and mental health, we tested BXD recombinant inbred strains previously found to show extreme contextual fear conditioning phenotypes and BXD parental strains, C57BL/6J and DBA/2J, in a series of tests including locomotor, anxiety, contextual/cued fear conditioning and non-associative hippocampus-dependent learning behaviors. Hippocampal expression of two previously identified candidate genes for contextual fear conditioning was also quantified. Behavioral and gene expression data were analyzed using exploratory factor analysis (EFA), which suggested five unique constructs representing activity/anxiety/exploration, associative fear learning, anxiety, post-shock freezing, and open field activity phenotypes. Associative fear learning and expression of one candidate gene, Hacd4, clustered as a construct within the factor analysis. Post-shock freezing during fear conditioning and expression of candidate gene Ptprd emerged as another unique construct, highlighting the independence of freezing after footshock from other fear conditioning variables in the current dataset. EFA results additionally suggest shared phenotypic variance in adaptive murine behaviors related to anxiety, general activity, and exploration. These findings inform understanding of fear learning and underlying biological mechanisms that may interact to produce individual differences in fear- and learning-related behaviors in mice.

There is now ample evidence that the strength and underlying mechanisms of memory formation can be drastically altered by prior experience. However, the prior work using rodent models on this topic has used only males as subjects, and as a result, we do know whether or not the effects of prior experience on subsequent learning are similar in both sexes. As a first step towards addressing this shortcoming, rats of both sexes were given auditory fear conditioning, or fear conditioning with unsignaled shocks, followed an hour or a day later by a single pairing of light and shock. Fear memory for each experience was assessed by measuring freezing behavior to the auditory cue and fear-potentiated startle to the light. Results showed that males trained with auditory fear conditioning showed facilitated learning to the subsequent visual fear conditioning session when the two training sessions were separated by one hour or one day. Females showed evidence of facilitation in rats given auditory conditioning when they were spaced by an hour but not when they were spaced by one day. Contextual fear conditioning did not support the facilitation of subsequent learning under any conditions. These results indicate that the mechanism by which prior fear conditioning facilitates subsequent learning differs between sexes, and they set the stage for mechanistic studies to understand the neurobiological basis of this sex difference.

Performing exercise before or after motor skill learning is thought to have a positive impact on acquisition and retention of motor memories stored in our nervous system. It has been shown that performing 25 min of moderate-intensity aerobic exercise prior to visuomotor adaptation can enhance both visuomotor adaptation and its retention compared to 25 min of rest before the adaptation. To determine whether a single bout of aerobic exercise could actually facilitate the formation of a neural representation associated with a novel visuomotor condition, we examined aftereffects and savings associated with a visuomotor adaptation task following either an exercise or a rest condition. Sixteen healthy young individuals (18–35 years) first experienced 25 min of moderate-intensity cycling or rest, and then adapted to a 30-degree visuomotor rotation condition. Immediately following that, participants experienced a washout session, which was followed by a readaptation session. Results indicated that all subjects adapted to the visuomotor rotation completely, although no difference was found between the cycling and rest conditions. Aftereffects and savings were also observed in both conditions, but with no difference between the conditions. These findings suggest that compared to a short rest session, a single bout of moderate-intensity cycling may not have a greater impact for enhancing visuomotor adaptation and its retention. Further research is needed, in which the effects of certain factors such as exercise intensity, duration and timing are more systematically investigated.

Hyperactive orbitofrontal cortical activation is commonly seen in patients of obsessive–compulsive disorder (OCD). Previous studies from our laboratory showed that for rats with aberrant activation of the orbitofrontal cortex (OFC) during the extinction phase, they were unable to use contexts as the reference for proper retrieval of fear memory during renewal test. This result supported the phenomenon that many OCD patients show poor regulation of fear-related behavior. Since there are robust anatomical connections of the OFC with the fear-circuit, we aim to further examine whether the OFC is actively engaged in fear regulation under normal circumstances. In this study, the lateral or medial OFC was inactivated during the extinction phase using the ABA fear renewal procedure. We found that these animals showed intact fear renewal during retrieval test with their freezing levels equivalent to the control rats, revealing that the OFC did not have decisive roles in extinction acquisition. Together with our previous study, we suggest that the OFC only interferes with fear regulation when it becomes pathophysiologically hyperactive.

Exposure to acute and chronic stress has significant effects on the basic mechanisms of associative learning and memory. Stress can both impair and enhance associative learning depending on type, intensity, and persistence of the stressor, the subject’s sex, the context that the stress and behavior is experienced in, and the type of associative learning taking place. In some cases, stress can cause or exacerbate the maladaptive behavior that underlies numerous psychiatric conditions including anxiety disorders, obsessive–compulsive disorder, post-traumatic stress disorder, substance use disorder, and others. Therefore, it is critical to understand how the varied effects of stress, which may normally facilitate adaptive behavior, can also become maladaptive and even harmful. In this review, we highlight several findings of associative learning and decision-making processes that are affected by stress in both human and non-human subjects and how they are related to one another. An emerging theme from this work is that stress biases behavior towards less flexible strategies that may reflect a cautious insensitivity to changing contingencies. We consider how this inflexibility has been observed in different associative learning procedures and suggest that a goal for the field should be to clarify how factors such as sex and previous experience influence this inflexibility.

The influence of the Rescorla-Wagner model cannot be overestimated, despite that (1) the model does not differ much computationally from its predecessors and competitors, and (2) its shortcomings are well-known in the learning community. Here we discuss the reasons behind its widespread influence in the cognitive and neural sciences, and argue that it is the constant search for general-process theories by learning scholars which eventually produced a model whose application spans many different areas of research to this day. We focus on the theoretical and empirical background of the model, the theoretical connections that it has with later developments across Marr’s levels of analysis, as well as the broad variety of research that it has guided and inspired.