Neurobiology of Learning and Memory最新文献

Environmental enrichment (EE) is a process of brain stimulation by modifying the surroundings, for example, by changing the sensory, social, or physical conditions. Rodents have been used in such experimental strategies through exposure to diverse physical, social, and exploration conditions. The present study conducted an extensive analysis of the existing literature surrounding the impact of EE on dementia rodent models. The review emphasised the two principal aspects that are very closely related to dementia: cognitive function (learning and memory) as well as psychological factors (anxiety-related behaviours such as phobias and unrealistic worries). Also highlighted were the mechanisms involved in the rodent models of dementia showing EE effects. Two search engines, PubMed and Science Direct, were used for data collection using the following keywords: environmental enrichment, dementia, rodent model, cognitive performance, and anxiety-related behaviour. Fifty-five articles were chosen depending on the criteria for inclusion and exclusion. The rodent models with dementia demonstrated improved learning and memory in the form of hampered inflammatory responses, enhanced neuronal plasticity, and sustained neuronal activity. EE housing also prevented memory impairment through the prevention of amyloid beta (Aβ) seeding formation, an early stage of Aβ plaque formation. The rodents subjected to EE were observed to present increased exploratory activity and exert less anxiety-related behaviour, compared to those in standard housing. However, some studies have proposed that EE intervention through exercise would be too mild to counteract the anxiety-related behaviour and risk assessment behaviour deficits in the Alzheimer's disease rodent model. Future studies should be conducted on old-aged rodents and the duration of EE exposure that would elicit the greatest benefits since the existing studies have been conducted on a range of ages and EE durations. In summary, EE had a considerable effect on dementia rodent models, with the most evident being improved cognitive function.

This series of experiments examined the effects of extinction and an explicitly unpaired treatment on the ability of a conditioned stimulus (CS) to function as a reinforcer. Rats were trained to lever press for food, exposed to pairings of a noise CS and food, and, finally, tested for their willingness to lever press for the CS in the absence of the food. Experiment 1 provided a demonstration of conditioned reinforcement (using controls that were only exposed to unpaired presentations of the CS and food) and showed that it was equivalent after one or four sessions of CS-food pairings. Experiments 2 and 3 showed that, after one session of CS-food pairings, repeated presentations of the CS alone reduced its reinforcing properties; but after four sessions of CS-food pairings, repeated presentations of the CS alone had no effect on these properties. Experiment 4 showed that, after four sessions of CS-food pairings, explicitly unpaired presentations of the CS and food completely undermined conditioned reinforcement. Finally, Experiment 5 provided within-experiment evidence that, after four sessions of CS-food pairings, the reinforcing properties of the CS were disrupted by explicitly unpaired presentations of the CS and food but spared by repeated presentations of the CS alone. Together, these findings indicate that the effectiveness of extinction in undermining the reinforcing properties of a CS depends on its level of conditioning; and that, where extinction fails to disrupt these properties, they are successfully undermined by an explicitly unpaired treatment. They are discussed with respect to findings in the literature on Pavlovian-to-instrumental transfer; and the Rescorla-Wagner model, which anticipates that an explicitly unpaired treatment will be more effective than extinction in reversing the effects of conditioning.

Classically interpreted as a competition between opposite memories (A vs B), anterograde interference (AI) also emerges in the absence of competing memories (A vs A), suggesting that mechanisms other than those involved in memory competition contribute to AI. To investigate this, we tested the hypothesis that extending motor practice would enhance a first memory, but come at the cost of reduced learning capabilities when subsequently exposed to a second learning session of the same task. Based on converging biological evidence, AI was expected to depend upon the degree of extended practice of the initial exposure. During a first Session, four conditions were carried out where participants (n = 24) adapted to a gradually introduced −20° visual deviation while the extent of the initial exposure was manipulated by varying the duration or type of the performance asymptote. Specifically, the performance asymptote at −20° was either Short (40 trials), Moderate (160 trials), Long (320 trials), or absent due to continuously changing perturbations around the mean of −20° (Jagged; 160 trials). After a 2-min interval, participants re-adapted to the same (-20°) visual deviation, which was meant to probe the effect of extended practice in the first Session on the learning capabilities of a second identical memory (A vs A). The results first confirmed that the duration of exposure in the first Session enhanced immediate aftereffects in the Moderate, Long, and Jagged conditions as compared to the Short condition, suggesting that extended practice enhanced retention of the first memory. When comparing the second Session to the first one, results revealed a different pattern of re-adaptation depending on the duration of initial exposure: in the Short condition, there was evidence for facilitated re-adaptation and similar aftereffects. However, in the Moderate, Long and Jagged conditions, re-adaptation was similar and aftereffects were impaired, suggestive of AI. This suggests that extended practice initially enhances memory formation, but comes at the cost of reduced subsequent learning capabilities. One possibility is that AI occurs because extended practice induces the emergence of network-specific homeostatic constraints, which limit subsequent neuroplastic and learning capabilities in the same neural network.

The orbitofrontal cortex (OFC) is often proposed to function as a value integrator; however, alternative accounts focus on its role in representing associative structures that specify the probability and sensory identity of future outcomes. These two accounts make different predictions about how this area should respond to conditioned inhibitors of reward, since in the former, neural activity should reflect the negative value of the inhibitor, whereas in the latter, it should track the estimated probability of a future reward based on all cues present. Here, we assessed these predictions by recording from small groups of neurons in the lateral OFC of rats during training in a conditioned inhibition design. Rats showed negative summation when the inhibitor was compounded with a novel excitor, suggesting that they learned to respond to the conditioned inhibitor appropriately. Against this backdrop, we found unit and population responses that scaled with expected reward value on excitor + inhibitor compound trials. However, the responses of these neurons did not differentiate between the conditioned inhibitor and a neutral cue when both were presented in isolation. Further, when the ensemble patterns were analyzed, activity to the conditioned inhibitor did not classify according to putative negative value. Instead, it classified with a same-modality neutral cue when presented alone and as a unique item when presented in compound with a novel excitor. This pattern of results supports the notion that OFC encodes a model of the causal structure of the environment rather than either the modality or the value of cues.

Animals rely on learned cues to guide their behaviour for rewards such as food. The Pavlovian-instrumental transfer (PIT) task can be used to investigate the influence of Pavlovian stimuli on instrumental responding. Ghrelin, an orexigenic peptide, and its receptor, growth hormone secretagogue receptor 1A (GHS-R1A), has received growing interest for its role in reward-motivated learning and behaviours. A significant population of GHS-R1A have been identified within the ventral tegmental area (VTA), a critical node in the mesolimbic reward circuit that is necessary for the expression of PIT. As ghrelin has been found to increase dopaminergic activity in the VTA, we predicted that GHS-R1A antagonism with JMV-2959 would attenuate PIT. Further, given the relationship between hunger levels and changes in ghrelin signalling, we sought to compare the effects GHS-R1A antagonism with those of satiety, hypothesizing parallel effects, with each attenuating PIT. Rats received daily sessions of Pavlovian and then instrumental training over 3 weeks. Across three experiments, we examined the effects of a shift to satiety, or treatment with the GHS-R1A antagonist JMV-2959, either peripherally or directly into the VTA. We found that presentations of a stimulus paired with food reward enhanced responding for food across all conditions, thus demonstrating the expected PIT effect. Further, GHS-R1A antagonism, both peripherally and within the VTA, as well as satiety significantly reduced the magnitude of the PIT effect compared to control conditions. These results clarify our understanding of ghrelin signalling in PIT and begin to elucidate the role of feeding-related peptides in the modulation of reward-related responding.

Preclinical studies show that inhibiting the actin motor ATPase nonmuscle myosin II (NMII) with blebbistatin (Blebb) in the basolateral amgydala (BLA) depolymerizes actin, resulting in an immediate, retrieval-independent disruption of methamphetamine (METH)-associated memory in male and female adult and adolescent rodents. The effect is highly selective, as NMII inhibition has no effect in other relevant brain regions (e.g., dorsal hippocampus [dPHC], nucleus accumbens [NAc]), nor does it interfere with associations for other aversive or appetitive stimuli, including cocaine (COC). To understand the mechanisms responsible for drug specific selectivity we began by investigating, in male mice, the pharmacokinetic differences in METH and COC brain exposure . Replicating METH’s longer half-life with COC did not render the COC association susceptible to disruption by NMII inhibition. Therefore, we next assessed transcriptional differences. Comparative RNA-seq profiling in the BLA, dHPC and NAc following METH or COC conditioning identified crhr2, which encodes the corticotropin releasing factor receptor 2 (CRF2), as uniquely upregulated by METH in the BLA. CRF2 antagonism with Astressin-2B (AS2B) had no effect on METH-associated memory after consolidation, allowing for determination of CRF2 influences on NMII-based susceptibility. Pretreatment with AS2B prevented the ability of Blebb to disrupt an established METH-associated memory. Alternatively, combining CRF2 overexpression and agonist treatment, urocortin 3 (UCN3), in the BLA during conditioning rendered COC-associated memory susceptible to disruption by NMII inhibition, mimicking the Blebb-induced, retrieval-independent memory disruption seen with METH. These results suggest that BLA CRF2 receptor activation during memory formation in male mice can prevent stabilization of the actin-myosin cytoskeleton supporting the memory, rendering it vulnerable to disruption by NMII inhibition. CRF2 represents an interesting target for BLA-dependent memory destabilization via downstream effects on NMII.

In female rats and humans, reproductive experience (i.e., pregnancy) alters the behavioral, hormonal and molecular substrates of fear extinction. Here, we assessed whether the role of a central neural substrate of fear extinction, the basolateral amygdala (BLA), also changes following reproductive experience. Nulliparous (virgin) and primiparous (one prior pregnancy) female rats received infusions of the GABA_A agonist, muscimol, to temporarily inactivate the BLA prior to fear conditioning or extinction training. In follow up experiments, the BLA was also inactivated immediately after extinction training. BLA inactivation impaired the acquisition and expression of conditioned fear in both nulliparous and primiparous rats. In nulliparous rats, BLA inactivation prior to or immediately after extinction training impaired extinction retention. In contrast, in primiparous rats, BLA inactivation prior to or immediately after extinction training did not impair extinction retention, despite suppressing freezing during extinction training. These results suggest that, consistent with past findings in males, the BLA is a central component of the neural circuitry of fear acquisition and its extinction in virgin female rats. However, after pregnancy, female rats no longer depend on the BLA to extinguish fear, despite requiring the BLA to acquire conditioned fear. Given that fear extinction forms the basis of exposure therapy for anxiety disorders in humans, the present findings may have clinical implications. To improve the efficacy of exposure therapy for anxiety disorders, we may need to target different mechanisms in females dependent on their reproductive history.

This paper describes the relationship between performance in a decision-making task and the emergence of task-relevant representations. Participants learnt two tasks in which the appropriate response depended on multiple relevant stimuli and the underlying stimulus-outcome associations were governed by a latent feature that participants could discover. We divided participants into good and bad performers based on their overall classification rate and computed behavioural accuracy for each feature value. We found that participants with better performance had a better representation of the latent feature space. We then used representation similarity analysis on Electroencephalographic (EEG) data to identify when these representations emerge. We were able to decode task-relevant representations in a time window emerging 700 ms after stimulus presentation, but only for participants with good task performance. Our findings suggest that, in order to make good decisions, it is necessary to create and extract a low-dimensional representation of the task at hand.

The hippocampus is usually associated with recall memory, whereas its contribution to familiarity-based memory is debated. Growing evidence support the idea that this structure participates to any cognitive process performed on scene representations. In parallel, differences in functional specialisation and cortical connectivity were found across the longitudinal and transverse axes of the hippocampus. Here we reanalysed functional MRI data from 51 participants showing stronger engagement of the hippocampus in recall, familiarity-based recognition and rejection, and visual discrimination, of scenes compared to single objects. A conjunction analysis between these four tasks revealed a set of occipital, medial temporal, posterior cingulate, and parietal regions, matching the scene construction network described in the literature. Crucially, we found that the anterior medial part of the hippocampus was consistently involved in all tasks investigated for scene stimuli. These findings support that the hippocampus can contribute to both recall and familiarity-based memory, depending on stimulus type. More generally, this bolsters the recent proposal that circumscribed regions within the hippocampus may underpin specific cognitive mechanisms.

The purpose of the present investigation was to test how acute stress and levels of circulating estrogens together influence acquisition and retention of spatial learning, as well as explorative behaviors in female rats. We used the hippocampus-dependent Open-field Tower Maze (OFTM) task to assess acquisition followed by a retention test (reacquisition) that was given 48 h later. Immediately prior to acquisition, experimental rats were exposed to an acute restraint stress and were trained under bright lights. Female rats’ estrous cycles were tracked throughout training and testing. Exposure to stress did not affect learning when levels of estrogens were low (i.e., during estrus and metestrus). However, acute stress exposure significantly lowered spatial acquisition of the female rats in the phases with rising levels of estrogens (i.e., during diestrus and proestrus). Furthermore, this stress-induced diminishment during acquisition was evident at the beginning of the retention without any presentation of stress. The present findings provide insight about the interactive relationship between stress and sex hormones on cognitive functions.