A stimulus that predicts the delivery of a specific food outcome can bias performance towards instrumental actions that earn that same outcome in a phenomenon known as specific Pavlovian-instrumental transfer (PIT). The precise mechanism by which the specific instrumental action is selected under these circumstances has remained elusive. The present set of experiments explored whether treatments that undermine the response-outcome (R-O) association also affect the expression of specific PIT. Consistent with previous work, in Experiment 1 we showed that specific PIT remains intact after an instrumental degradation treatment that attempted to undermine R-O associations. However, we additionally demonstrated that outcome-devaluation sensitivity also persisted after degradation, suggesting that R-O associations were impervious to the degradation treatment, and precluding any conclusions about the necessity of R-O associations for specific PIT expression. Nevertheless, given the two-lever two-outcome design of this experiment it is possible that R-O associations were indeed undermined by degradation and that the devaluation effect was driven by distinct, incidental Pavlovian lever-outcome associations. To nullify the obscuring effects of these incidental Pavlovian associations, we used a bidirectional lever for instrumental conditioning that could be pushed to the left or the right for distinct outcomes. In Experiment 2 we demonstrated that specific PIT could be observed on this bidirectional manipulandum whether the subjects were hungry or sated, consistent with the literature. The critical third Experiment used an identical design to Experiment 1 except that the two instrumental responses were made on the single bidirectional manipulanda. Here, specific PIT was intact after instrumental degradation and, crucially, we saw no evidence of outcome devaluation sensitivity in these same subjects, suggesting that the R-O associations were weakened or undermined by this treatment. We conclude that the expression of specific PIT is resistant to treatments that undermine R-O associations and disrupt value based choice, and discuss how these findings contribute to our understanding of the associative framework supporting behavioral control.

Prediction and memory are strongly intertwined, with predictions relying on memory retrieval, whilst also influencing memory encoding. However, it is unclear how predictability influences explicit memory performance, and how individual neural factors may modulate this relationship. The current study sought to investigate the effect of predictability on memory processing with an analysis of the N400 event-related potential in a context extending beyond language. Participants (N = 48, females = 33) completed a study-test paradigm where they first viewed predictable and unpredictable four-item 'ABCD' sequences of outdoor scene images, whilst their brain activity was recorded using electroencephalography. Subsequently, their memory for the images was tested, and N400 patterns during learning were compared with memory outcomes. Behavioural results revealed better memory for images in predictable sequences in contrast to unpredictable sequences. Memory was also strongest for predictable images in the 'B' position, suggesting that when processing longer sequences, the brain may prioritise the data deemed most informative. Strikingly, greater N400 amplitudes during learning were associated with enhanced memory at test for individuals with low versus high individual alpha frequencies. In light of the relationship between the N400 and stimulus predictability, this finding may imply that predictive processing differs between individuals to influence the extent of memory encoding. Finally, exploratory analyses provided evidence for a later positivity that was predictive of subsequent memory performance. Ultimately, the results highlight the complex and interconnected relationship between predictive processing and memory, whilst shedding light on the accumulation of predictions across longer sequences.

The retrosplenial cortex (RSC) plays an important role in spatial cognition. RSC neurons exhibit a variety of spatial firing patterns and lesion studies have found that the RSC is necessary for spatial working memory tasks. However, little is known about how RSC neurons might encode spatial memory during a delay period. In the present study, we trained control rats and rats with excitotoxic lesions of the RSC on spatial alternation task with varying delay durations and in a separate group of rats, we recorded RSC neuronal activity as the rats performed the alternation task. We found that RSC lesions significantly impaired alternation performance, particularly at the longest delay duration. We also found that RSC neurons exhibited reliably different firing patterns throughout the delay periods preceding left and right trials, consistent with a working memory signal. These differential firing patterns were absent during the delay periods preceding errors. We also found that many RSC neurons exhibit a large spike in firing rate leading up to the start of the trial. Many of these trial start responses also differentiated left and right trials, suggesting that they could play a role in priming the 'go left' or 'go right' behavioral responses. Our results suggest that these firing patterns represent critical memory information that underlies the RSC role in spatial working memory.

Although early studies were able to demonstrate a negative impact of stress on working memory performance, present research findings are heterogeneous. Numerous further studies found no effects or even improved performance, with the direction of these stress effects likely depending on the underlying biological mechanisms. The aim of this study was to investigate receptor-specific effects, as part of the stress-induced cortisol response, on working memory performance. Healthy, male participants (N=318, mean age 25.4 ± 5.1y) were exposed to the Trier Social Stress Test (TSST), a social-evaluative stress manipulation, or a non-stress control condition after they had received either spironolactone (blockade of the mineralocorticoid receptor, MR) or mifepristone (blockade of the glucocorticoid receptor, GR) or a placebo. Both substances are potent antagonists with high affinity for the respective receptors. To assess working memory, we implemented the n-back task subsequent to stress exposure, number of correct responses and reaction times served as outcome measures. We did not find effects of stress on working memory for any outcome measure, i.e. correct responses and reaction times. Yet, post hoc tests revealed that the group that received mifepristone exhibited longer reaction times under medium load conditions when compared to the placebo group, which might be an indication of the GR's involvement in task performance. We conclude that working memory performance is not affected by acute stress, at least under these prevalent conditions.

The basolateral amygdala (BLA) modulates different types of memory consolidation via distinct projections to downstream brain regions in multiple memory systems. Prior studies indicate that the BLA projects to the nucleus accumbens shell (NAshell) and that these regions interact to influence some types of behavior. Moreover, previous pharmacological work suggests the BLA and NAshell interact to influence memory. However, the precise role of the BLA-NAshell pathway has never been directly investigated in the consolidation of different types of memory including cued-response, spatial, or inhibitory avoidance (IA) learning. To address this, male and female Sprague-Dawley rats received optogenetic manipulations of the BLA or BLA-NAshell pathway immediately following training in different learning tasks. An initial experiment found that optogenetically inhibiting the BLA itself immediately after training impaired cued-response retention in a Barnes maze task in males and females, confirming earlier pharmacological work in males alone. Subsequent experiments found that BLA-NAshell pathway inhibition impaired retention of cued-response and IA learning but had no effect on retention of spatial learning. However, the present work did not observe any effects of pathway stimulation immediately after cued-response or IA learning. Together, the present findings suggest the BLA modulates the consolidation of cued-response and IA, but not spatial, memory consolidation via NAshell projections.

Humans and animals can quickly learn a new strategy when a previously-rewarding strategy is punished. It is difficult to model this with reinforcement learning methods, because they tend to perseverate on previously-learned strategies - a hallmark of impaired response to punishment. Past work has addressed this by augmenting conventional reinforcement learning equations with ad hoc parameters or parallel learning systems. This produces reinforcement learning models that account for reversal learning, but are more abstract, complex, and somewhat detached from neural substrates. Here we use a different approach: we generalize a recently-discovered neuron-level learning rule, on the assumption that it captures a basic principle of learning that may occur at the whole-brain-level. Surprisingly, this gives a new reinforcement learning rule that accounts for adaptation and lose-shift behavior, and uses only the same parameters as conventional reinforcement learning equations. In the new rule, the normal reward prediction errors that drive reinforcement learning are scaled by the likelihood the agent assigns to the action that triggered a reward or punishment. The new rule demonstrates quick adaptation in card sorting and variable Iowa gambling tasks, and also exhibits a human-like paradox-of-choice effect. It will be useful for experimental researchers modeling learning and behavior.

Reinforcement learning, crucial for behavior in dynamic environments, is driven by rewards and punishments, modulated by dopamine (DA) changes. This study explores the dopaminergic system's influence on learning, particularly in Parkinson's disease (PD), where medication leads to impaired adaptability. Highlighting the role of tonic DA in signaling the valence of actions, this research investigates how DA affects response vigor and decision-making in PD. DA not only influences reward and punishment learning but also indicates the cognitive effort level and risk propensity in actions, which are essential for understanding and managing PD symptoms. In this work, we adapt our existing neurocomputational model of basal ganglia (BG) to simulate two reversal learning tasks proposed by Cools et al. We first optimized a Hebb rule for both probabilistic and deterministic reversal learning, conducted a sensitivity analysis (SA) on parameters related to DA effect, and compared performances between three groups: PD-ON, PD-OFF, and control subjects. In our deterministic task simulation, we explored switch error rates after unexpected task switches and found a U-shaped relationship between tonic DA levels and switch error frequency. Through SA, we classify these three groups. Then, assuming that the valence of the stimulus affects the tonic levels of DA, we were able to reproduce the results by Cools et al. As for the probabilistic task simulation, our results are in line with clinical data, showing similar trends with PD-ON, characterized by higher tonic DA levels that are correlated with increased difficulty in both acquisition and reversal tasks. Our study proposes a new hypothesis: valence, signaled by tonic DA levels, influences learning in PD, confirming the uncorrelation between phasic and tonic DA changes. This hypothesis challenges existing paradigms and opens new avenues for understanding cognitive processes in PD, particularly in reversal learning tasks.

Cue-potentiated feeding (CPF) describes instances where food intake is increased by exposure to conditioned cues associated with food, often in the absence of hunger. CPF effects have been reported in a range of experimental protocols developed by researchers working across diverse fields spanning behavioural neuroscience, social psychology and ecology. Here we review the evolution of research on cue-potentiated feeding in animal models to identify important behavioural parameters and key neural circuits and pharmacological systems underlying the effect. Overall, evidence indicates that social, discrete and contextual stimuli can be used to elicit CPF effects across multiple species, though effects are often subtle and sensitive to procedural variables. While regular exposure to food cues is thought to be a key risk factor for overeating in so-called 'obesogenic' environments, further work is needed to identify whether CPF promotes positive energy balance and weight gain over the longer term. We suggest several methodological and conceptual areas for inquiry to elucidate the contribution of CPF to the regulation of food choice and energy intake.

The retrosplenial cortex (RSC) plays a critical role in complex cognitive functions such as contextual fear memory formation and consolidation. Perineuronal nets (PNNs) are specialized structures of the extracellular matrix that modulate synaptic plasticity by enwrapping the soma, proximal neurites and synapsis mainly on fast spiking inhibitory GABAergic interneurons that express parvalbumin (PV). PNNs change after contextual fear conditioning (CFC) in amygdala or hippocampus, yet it is unknown if similar remodeling takes place at RSC. Here, we used Wisteria floribunda agglutinin (WFA), a ubiquitous marker of PNNs, to study the remodeling of PNNs in RSC during the acquisition or retrieval of contextual fear conditioning (CFC). Adult male mice were exposed to paired presentations of a context and footshock, or to either of these stimuli alone (control groups). The mere exposure of animals to the footshock, either alone or paired with the context, evoked a significant expansion of PNNs, both in the number of WFA positive neurons and in the area occupied by WFA staining, across the entire RSC. This was not associated with c-Fos expression in RSC nor correlated with c-Fos expression in individual PNNs-expressing neurons in RSC, suggesting that PNNs remodeling is triggered by inputs external to the RSC. We also found that PNNs remodeling was independent of the level of PV expression. Notably, PNNs in RSC remained expanded long-after CFC. These results suggest that, in male mice, the threatening experience is the main cause of PNNs remodeling in the RSC.

The ability to form long-term memories begins in early infancy. However, little is known about the specific mechanisms that guide memory formation during this developmental stage. We demonstrate the emergence of a long-term memory for a novel voice in three-month-old infants using the EEG mismatch response (MMR) to the word "baby". In an oddball-paradigm, a frequent standard, and two rare deviant voices (novel and mother) were presented before (baseline), and after (test) familiarizing the infants with the novel voice and a subsequent nap. Only the mother deviant but not the novel deviant elicited a late frontal MMR (∼850 ms) at baseline, possibly reflecting a long-term memory representation for the mother's voice. Yet, MMRs to the novel and mother deviant significantly increased in similarity after voice familiarization and sleep. Moreover, both MMRs showed an additional early (∼250 ms) frontal negative component that is potentially related to deviance processing in short-term memory. Enhanced spindle activity during the nap predicted an increase in late MMR amplitude to the novel deviant and increased MMR similarity between novel and mother deviant. Our findings indicate that the late positive MMR in infants might reflect emergent long-term memory that benefits from sleep spindles.

In laboratories, classical fear conditioning and extinction procedures are commonly used to study the behavioral and neural mechanisms underlying fear regulation. Contextual fear conditioning involves the association of an aversive event with the environment where it occurs, which engages the hippocampus and its interactions with the amygdala. The orbitofrontal cortex (OFC), divided into the lateral OFC (lOFC) and medial OFC (mOFC) subregions, plays a crucial role in integrating contextual information from the hippocampus and modulating behavioral responses based on the anticipated outcomes of the context. Because of the extensive anatomical connections of the OFC with the fear circuit, including the hippocampus, the amygdala, and the medial prefrontal cortex, and the reasoning that proper retrieval of fear-related memory is context-dependent, we raised the question to investigate the ability of the animals to discriminate between contexts when they were trained under differential OFC activation levels during the encoding of contextual fear memory. In this study, we conducted a contextual fear conditioning procedure in rats using footshock as an unconditioned stimulus (US), followed by the test of their fear levels in contexts same (dangerous) or different (safe) from the conditioning context. We used a pharmacological approach to modulate the activation levels of the lOFC or the mOFC during conditioning to examine their roles on context-specific fear encoding. Our findings showed that the animals could accurately distinguish between the two contexts in control and OFC hypoactivation groups, but failed to do so if they were trained under OFC hyperactivation. Therefore, OFC hyperactivity disturbed the encoding of contextual information during fear acquisition.

Several leading therapies for anxiety-related disorders rely on the principles of extinction learning. However, despite decades of development and research, many of these treatments remain only moderately effective. Developing techniques to improve extinction learning is an important step towards developing improved and mechanistically-informed exposure-based therapies. In this review, we highlight human research on strategies that might augment extinction learning through reward neurocircuitry and dopaminergic pathways, with an emphasis on counterconditioning and other behaviorally-augmented forms of extinction learning (e.g., novelty-facilitated extinction, positive affect training). We also highlight emerging pharmacological and non-pharmacological methods of augmenting extinction, including L-DOPA and aerobic exercise. Finally, we discuss future directions for augmented extinction learning and memory research, including the need for more work examining the influence of individual differences and psychopathology.

Certain object properties may render an item as more memorable than others. One such property is manipulability, or the extent to which an object can be interacted with using our hands. This study sought to determine if the manipulability of an item modulates memory task performance on both a behavioural and neural level. We recorded electroencephalography (EEG) from a large sample of right-handed individuals (N = 53) during a visual item recognition memory task. The task contained stimuli of both high and low manipulability. Analysis focused on activity in the theta rhythm (3.5-7 Hz), which has been implicated in sensorimotor integration, and the mu rhythm (8-14 Hz), the primary oscillation associated with sensorimotor related behaviours. At both encoding and retrieval, theta oscillations were greater over the left motor region for high manipulability stimuli, suggesting that an item's sensorimotor properties are assessed immediately upon presentation. Manipulability did not affect activity in the mu rhythm. However, mu oscillations over the left motor region were lower during the retrieval of old versus new items and response time was faster for old items, aligning with the cortical reinstatement hypothesis. These results collectively reveal an association between motor oscillations and memory processes, highlight the involvement of sensorimotor processing at both encoding and retrieval.

Exercise provides a range of cognitive benefits, including improved memory performance. Previously, we demonstrated that 14 days of continuous voluntary wheel-running exercise enables learning in a hippocampus-dependent Object Location Memory (OLM) task under insufficient, subthreshold training conditions in adult mice. Whether similar exercise benefits can be obtained from consistent intermittent exercise as continuous exercise is unknown. Here, we examine whether intermittent exercise (the weekend warrior effect: 2 days of exercise a week for 7 weeks) displays similar or distinct cognitive benefits as previously examined with 14 days of continuous exercise. We find that both continuous and intermittent exercise parameters similarly enable hippocampus-dependent OLM compared to the 2-day exercise control group. Mice receiving intermittent exercise maintained cognitive benefits following a 7-day sedentary delay, whereas mice that underwent 14 continuous days of exercise showed diminished cognitive benefits as previously reported. Further, compared to continuous exercise, intermittent exercise mice exhibited persistently elevated levels of the genes Acvr1c and Bdnf which we know to be critically involved in hippocampus-dependent long-term memory in the dorsal hippocampus. Together findings suggest that consistent intermittent exercise persistently enables hippocampal-dependent long-term memory. Understanding the optimal parameters for persistent cognitive function and the mechanisms mediating persistent effects will aid in therapeutic pursuits investigating the mitigation of cognitive ailments.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that can alter the state of the stimulated brain area and thereby affect neurocognitive processes and resulting behavioural performance. Previous studies have shown disparate results with respect to tDCS effects on language function, particularly with respect to language learning and word acquisition. To fill this gap, this study aimed at systematically addressing the effects of tDCS of core left-hemispheric language cortices on the brain mechanisms underpinning two main neurocognitive strategies of word learning: implicit inference-based Fast Mapping (FM) and direct instruction-based Explicit Encoding (EE). Prior to a word-learning session, 160 healthy participants were given 15 min of either anodal or cathodal tDCS of Wernicke's or Broca's areas, or a control sham (placebo) stimulation, using a between-group design. Each participant then learned 16 novel words (8 through FM and 8 through EE) in a contextual word-picture association session. Moreover, these words were learnt either perceptually via auditory exposure combined with a graphical image of the novel object, or in an articulatory mode, where the participants additionally had to overtly articulate the novel items. These learning conditions were fully counterbalanced across participants, stimuli and tDCS groups. Learning outcomes were tested at both lexical and semantic levels using two tasks: recognition and word-picture matching. EE and FM conditions produced similar outcomes, indicating comparable efficiency of the respective learning strategies. At the same time, articulatory learning produced generally better results than non-articulatory exposure, yielding higher recognition accuracies and shorter latencies in both tasks. Crucially, real tDCS led to global outcome improvements, demonstrated by faster (compared to sham) reactions, as well as some accuracy changes. There was also evidence of more specific tDCS effects: better word-recognition accuracy for EE vs. FM following cathodal stimulation as well as more expressed improvements in recognition accuracy and reaction times for anodal Broca's and cathodal Wernicke's stimulation, particularly for unarticulated FM items. These learning mode-specific effects support the notion of partially distinct brain mechanisms underpinning these two learning strategies. Overall, numerically largest improvements were observed for anodal Broca's tDCS, whereas the least expressed benefits of tDCS for learning were measured after anodal Wernicke stimulation. Finally, we did not find any inhibitory effects of either tDCS polarity in any of the comparisons. We conclude that tDCS of core language areas exerts a general facilitatory effect on new word acquisition with some limited specificity to learning protocols - the result that may be of potential applied value for future research aimed at ameliorating learning deficits and language disorders.

Studies on memory engram have demonstrated how experience and learning can be allocated at a neuronal level for centuries. Recently emerging evidence narrowed down further to the synaptic connections and their patterned allocation on dendrites. Notably, groups of synapses within a specific range within dendrites known as 'synaptic clusters' have been revealed in association with learning and memory. Previous investigations have shown that a variety of factors mediated by both presynaptic inputs and postsynaptic dendrites contribute to clustering. Here, we review the neural mechanism of synaptic clustering and its correlation with memory. We highlight the recent findings about the clustering of synaptic engrams and memory formation and discuss future directions.

Memory retrieval has been extensively studied in relation to the encoding processes that precede access to stored information. Event related potentials (ERP) research has compared brain potentials elicited during the study phase of successful and unsuccessful retrieval, finding greater activation for the subsequent retrieval information. In this work we were interested in exploring the neural markers associated to subsequent recognition when similar memories are subsequently encoded. We used a Subsequent Memory paradigm in which we manipulated the number of similar items within a category (2 or 6) that participants encoded. Manipulating the number of similar encoded items within a category allowed us to test whether encoding markers of subsequent recognition depend solely on memory trace strength or, on the contrary, successful recognition is influenced by subsequently presented similar memories, and consequently may not be reflected in higher activation in such cases. After a 20-minute period, participants performed a recognition task providing one of a three-option judgement: "old", "similar" and "new", which allowed us to test if the amplitude of ERP waveforms varied based on the similarity judgement of the unrecognized encoded item. We did not observe a significant parietal subsequent memory effect, however, old hits and similar false alarms were both significantly different from similar correct rejections and old false alarms in ERP retrieval. These findings suggest that differences in brain responses between conditions are specifically related to the retrieval process and not the encoding process, indicating potential differential effects on memory during retrieval. Moreover, it is also possible that differences in brain responses develop or change over the rest time between phases, influencing how these conditions manifest across different stages of information processing.

Habitual instrumental behaviour is believed to rely on stimulus-response (S-R) associations. However, the method most commonly used to identify habitual behaviour, outcome devaluation, provides only indirect evidence of S-R control. Therefore, it is important to have a better understanding of the S-R association believed to underlie habitual responding. Under free-operant conditions, the context itself likely serves as at least part of the relevant stimuli in the association, and so modifications to the predictive power of the context should alter the expression of habits. The following experiments investigated how changes to the relationship between the training context and performance of the response, either by changing the context during testing or by exposing animals to the context alone, without the response lever present, impacted behavioural control during a devaluation test. We found evidence that the training context is important for the expression of habits; testing animals in a different context than where they were trained resulted in increased goal-directed control (Experiment 1). Furthermore, context alone exposure also increased goal-directed control with animals that received context alone exposure showing stronger devaluation effects, whether the context alone exposure happened on the last day of training (Experiment 2) or throughout training (Experiment 3). These findings are consistent with prior reports that the training context is important for the expression of habits and extends these findings by using sensory-specific satiety as a means for devaluation and by using context alone exposure to alter behavioural control.

The human posterior parietal cortex (PPC) is known to support sustained attention. Specifically, top-down attention is generally processed in dorsal regions while bottom-up regulation occurs more ventrally. In rodent models, however, it is still unclear whether the PPC is required for sustained attention, or whether there is a similar functional dissociation between anatomical regions. Consequently, the aim of this study was to investigate the contribution of the rodent dorsal PPC (dPPC) in sustained attention. We used the five-choice serial reaction time task (5CSRTT) and compared rats with neurotoxic dPPC lesions to sham operated rats. We found that rats with dPPC lesions were less accurate and took longer to make correct choices, indicating impaired attention and reduced processing speed. This effect, however, was limited to the first few days of post-operative testing. After an apparent recovery, omissions became elevated in the lesion group, which, in the absence of reduced motivation and mobility, can also be interpreted as impaired attention. In subsequent challenge probes, the lesion group displayed globally elevated latency to make a correct response, indicating reduced processing speed. No differences in premature responses or perseverative responses were observed at any time, demonstrating that dPPC lesions did not affect impulsivity and compulsivity. This pattern of behavior suggests that while intact dPPC supports goal-driven (top-down) modulation of attention, it likely does not play a central role in processing stimulus-driven (bottom-up) attention. Furthermore, compensatory mechanisms can support sustained attention in the absence of a fully functioning dPPC, although this occurs at the expense of processing speed. Our results inform the literature by confirming that rodent PPC is involved in regulating sustained attention and providing preliminary evidence for a functional dissociation between top-down and bottom-up attentional processing.