Learning & Memory

Temporal Order Memory (TOM), the ability to discriminate between events according to when they occurred, is a key component of episodic-like memory. Understanding the molecular mechanisms that support temporal memory requires behavioral approaches capable of capturing the continuous dynamics of natural exploration. Despite extensive evidence implicating the prefrontal cortex (PFC) in temporal memory, the intracellular signaling mechanisms supporting temporal order discrimination remain poorly understood. Here, we combined high-resolution automated behavioral phenotyping with molecular analyses to characterize the behavioral and signaling dynamics underlying TOM in mice. Mice were trained in a spontaneous object-recognition TOM task and tested after short-term (3 h) or long-term (24 h) retention intervals. Exploration was quantified using an artificial intelligence-based behavioral analysis pipeline that enables continuous and unbiased assessment of object exploration. Phosphorylation of extracellular signal-regulated kinase 2 (ERK2) and expression of the ERK phosphatase MKP3/DUSP6 were analyzed in the PFC and hippocampus (HIP) following habituation, a single training session, or two sequential training sessions. Additionally, a Temporal Novel Object Recognition (TeNOR) protocol was used to evaluate the integrity of memory traces. Mice displayed robust TOM performance across sexes and retention intervals. Molecular analyses revealed no significant changes in hippocampal ERK signaling, whereas the cytosolic fraction of the PFC exhibited dynamic, experience-dependent modulation of ERK2 phosphorylation. A single 15-minute training session induced a transient increase in ERK2 activation, while a second session 45 minutes later actively suppressed this peak. This rapid molecular reset was accompanied by increased MKP3 expression, suggesting the targeted recruitment of an active regulatory feedback mechanism. Continuous behavioral tracking further revealed temporal features of memory expression that were not captured by conventional summary measures; it identified an early, rapid decay of discrimination for older object memories in the TeNOR task, suggesting that TOM performance relies on resolving competitive retrieval between co-existing memory traces. Together, these findings identify dynamic ERK2-MKP3 signaling in the PFC as the molecular substrate upon which temporal discrimination can take place, and demonstrate how high-resolution phenotyping in naturalistic behavioral paradigms can reveal mechanistic links between intracellular signaling and the temporal organization of experience.

Long-term memory has been extensively documented in many animals across a range of ecological contexts. Far less is understood, however, about how long memories persist after active modification or how conflicting memories are adaptively regulated to enable flexible behaviour. Parrots are widely recognized for their high intelligence and cognitive capability, yet the study of memory has focused on only a handful of large parrot species. Here, using a binary choice symbolic system, we conducted three experiments on 28 rosy-faced lovebirds (Agapornis roseicollis) to investigate (1) memory retention of initial associative learning at intervals of two weeks, half a year, and one year; (2) reversal learning, where the rewarded and unrewarded symbols were swapped; and (3) memory retention, following reversal learning at two-week and half-year intervals. We revealed that (a) initial associative learning memory was strikingly persistent, remaining detectable after nearly 600 days; (b) reversal learning performance was comparable to that of large parrot species; and (c) while the post-reversal forgetting curve mirrored the pattern of initial learning, it exhibited a shorter retention duration and a lower retention plateau. These findings suggest that forgetting may serve as an adaptive mechanism that regulates the retrievability of conflicting information, rather than a simple erasure of memory traces. When the environment changes, the retrievability of previously functional but now maladaptive memories is suppressed, but their long-term storage is preserved for potential future use under analogous circumstances. Such dynamic regulations prevent the repetitive overwriting of information in a fluctuating environment, thereby fostering greater behavioural flexibility across dynamic scenarios.

RationaleAppetitive Pavlovian cues can drive maladaptive reward seeking via stimulus-reward memories. Disrupting memory reconsolidation offers a potential strategy to reduce their influence, but evidence for {beta}-adrenergic blockade with propranolol is inconsistent across behavioural paradigms, particularly relative to NMDA receptor antagonism. ObjectivesWe tested whether propranolol disrupts reconsolidation of appetitive sucrose memories in a discriminative goal-tracking paradigm, and compared its effects with those of the most commonly used NMDA receptor antagonist, MK-801. MethodsAdult Lister hooded rats underwent discriminative Pavlovian conditioning. Thirty minutes before a brief memory reminder (non-reinforced or reinforced), rats received systemic drug treatment or saline control. In study 1, MK-801 (0.1 mg/kg) was administered to male rats. In study 2, propranolol (10 mg/kg) was administered to equal numbers of male and female rats. Goal-tracking was tested drug-free at 1 and 8 days. ResultsIn study 1, MK-801 impaired subsequent discriminated responding at test. These effects were observed not only when reminder was non-reinforced as in previous successful demonstrations, but also with reinforced reminder. In study 2, Propranolol also impaired subsequent goal-tracking, regardless of reminder type, and the effects were consistent across sexes. ConclusionsPropranolol can disrupt reconsolidation of appetitive goal-tracking memories to a similar extent as MK-801 under conditions that promote memory destabilisation. These findings demonstrate that {beta}-adrenergic blockade can impair appetitive memory reconsolidation in a goal-tracking paradigm, challenging prior null findings and revitalising the potential for propranolol-based interventions in maladaptive reward-seeking behaviours.

RationaleAdaptive behavior requires revising memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear. ObjectivesWe tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration provides a behavioral readout consistent with successful updating of spatial information MethodsUsing inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was introduced. ResultsControl mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test. ConclusionsThese results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations. Significance StatementUsing a spatial paradigm that distinguishes detection of changed information from incorporation of that information into an updated hippocampal representation, we found that ventrolateral orbitofrontal cortex (VLO) activity is required for memory-updating when new information is present. We found behavioral deficits accompanied by impairments in hippocampal ensemble representations, indicating VLO activity is necessary for memory-updating at the hippocampal engram level. Through this mechanism, the OFC supports the flexible updating of expected outcomes when environmental conditions shift, allowing for the re-evaluation of previously learned associations. These findings extend models of orbitofrontal cortex function beyond reward-guided behavior and identify a cortical contribution to predictive spatial memory processes. Disruption of this computation may contribute to the cognitive rigidity observed in neuropsychiatric disorders.

Infantile amnesia refers to the inability to recall early-life experiences, despite their lasting influence on adult behavior. Recent evidence suggests that memory traces formed during infancy may persist in a silent engram state. However, whether and how these silent engram cells contribute to adult memory formation remains unclear. To address this, we examined whether experiences during infancy affect adult memory formation using contextual fear conditioning in mice. Consistent with previous studies, we observed infantile amnesia 30 days later. Despite amnesia, these mice exhibited memory enhancement upon retraining as adults, suggesting that silent infantile engrams influence adult memory. Notably, this effect was context-specific. Using a cellular tagging system and ablation approaches, we found that infantile engram cells in the infralimbic cortex (IL) were crucial for this memory enhancement. Overall, these findings demonstrate that infant engram cells in the IL are re-recruited into adult memory traces, providing a neural mechanism by which early-life experiences shape adult memory formation through relearning.

Foraging animals must continually evaluate whether potential food sources are safe to consume. Such decisions rely on both innate preferences and learned associations formed through prior experience. Consumption of a food followed by malaise or sickness leads to avoidance of that food, reflecting learned associations between sensory cues that identify a food and its negative post-ingestive consequences. Although this form of learning has been studied extensively using taste cues, taste signals arise only after oral contact, at which point exposure to potential toxins has already occurred. Olfactory cues, in contrast, provide information about potential food sources prior to consumption, yet how odors acquire aversive value remains unclear. Here, using targeted chemogenetic perturbations, we identify the nucleus of the lateral olfactory tract (NLOT), which has direct bidirectional connectivity to olfactory regions and the basolateral amygdala, as a critical circuit element for odor-aversion learning. We find that the NLOT is required for conditioned odor aversion but is dispensable for other odor-guided behaviors and for fear conditioning driven by a non-olfactory cue. Our findings identify a selective role for the NLOT in linking olfactory cues to learned aversive outcomes, that supports odor-guided behavioral decisions. Significance statementAnimals rely on smell to evaluate food safety before consuming it, yet the brain circuits that link odor cues to learned aversive outcomes remain poorly understood. Here we identify the nucleus of the lateral olfactory tract (NLOT), a largely unstudied region at the interface between olfactory and limbic circuits, as a critical and selective node for conditioned odor aversion learning. Chemogenetic perturbations of the NLOT disrupted both the acquisition and expression of odor-malaise associations, while leaving odor detection, odor discrimination, and non-olfactory fear learning intact -- revealing a previously unrecognized specialization within olfactory-amygdala circuits that supports odor-guided decisions about food safety.

Reinforced conditioning allows individuals predicting future events with high confidence. However, many daily behaviours rely on unreinforced connections of neutral stimuli, called Incidental Associations (IAs), which enhance predictive capacity in unstable environments and are observed across species. IAs can be studied through sensory preconditioning paradigms, where two neutral stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation during preconditioning. Our previous work demonstrated that type-1 cannabinoid receptors (CB1 receptors) in the hippocampus are essential for this IA formation. As dopamine signaling is also important for this process, we investigate the role of interactions between these dopamine-cannabinoid systems in IA memory formation in the hippocampus. Extending our previous work on odor-taste association, using light-sound association we showed that global CB1 receptor knock-out or specific hippocampal CB1 receptor deletion also blocked mediated responses to sound (S2) while direct response to light (S1) was unaltered. Focusing on dopamine, we then found hippocampal dopaminergic activity is enhanced during paired presentations of S1 and S2 and that blockade of dopamine D1 receptor during preconditioning S1-S2 associations abolished mediated response to S2. Interestingly, mice lacking CB1 receptors specifically in D1-receptor-expressing cells (D1-CB1-KO) failed to show mediated responses for either light-sound or odor-taste associations, identifying this CB1 receptor population as critical for IA formation. Enhanced activation of CB1 receptors, through either increase of endocannabinoids (using degradation enzyme inhibition) or exogenous stimulation by cannabis-derived Delta-9-tetrahydrocannabinol (THC), was able to promote the formation of IAs under insufficient conditions. The effect of endogenous CB1 activation, but not THC, was blocked in D1-CB1-KO mice indicating that IA-facilitation by endogenous and exogenous receptor activation rely on different mechanisms. Overall, these data uncover new mechanisms underlying unreinforced associative learning.

Animals detect and evaluate signs of danger and safety in their environment to ensure survival, yet the neural mechanisms that distinguish safety learning from other forms of conditioned inhibition, remain poorly understood. Here, we directly compared fear and safety learning in male rats. Fear conditioned rats showed high freezing to the tone and the conditioning context, whereas safety conditioned rats showed significant tone-specific reduction in freezing. This safety cue could also generalize to a novel, previously unassociated threat context leading to suppressed freezing when presented demonstrating that inhibitory actions of safety cues are not tied to its original training environment but can modify fear expression across settings. Fear and safety learning also produced unique patterns of neuronal activation and glutamatergic receptor expression in the medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and central amygdala (CeA), as measured by c-Fos immunohistochemistry and Western blotting. Fear conditioning induced greater Fos expression in the BLA and CeA, as well as elevated amygdalar NMDA receptor (GluN1) levels, whereas safety learning increased amygdalar PSD-95 and AMPA receptor (GluA1) expression. Both safety and fear learning increased mPFC Fos expression without affecting glutamatergic receptors levels. Finally, safety conditioning was associated with lower tone-evoked freezing than fear conditioned rats across early extinction sessions and was accompanied by distinct patterns of prefrontal and amygdala activation across extinction. Together, these findings suggest that safety learning engages neural and behavioral mechanisms distinct from fear learning and extinction, while modifying amygdala-prefrontal circuits towards more rapid fear suppression.

Working memory has been considered a delay-dependent retention system, but variability in delay duration across species and tasks suggests that task-intrinsic factors may also contribute. Here, we investigated the effects of delay duration (75 s vs. 150 s) and task distance (0 m vs. 2 m) on working memory using a T-maze delayed alternation task with a movable home-cage apparatus in rats. At the 150-s delay, accuracy was 9% lower at 0 m than at 2 m (75% vs. 84%), with a similar numerical tendency observed at the 75-s delay (4% lower). A two-way repeated measures ANOVA revealed significant main effects of both task distance and delay duration, with no significant interaction (p = 0.217). Post hoc pairwise comparisons indicated that accuracy in the 0-m condition was significantly lower at 150 s than at 75 s (adjusted p = 0.038). At the 150-s delay, accuracy was also significantly lower in the 0-m condition than in the 2-m condition (adjusted p = 0.019). These results suggest that working memory retention is influenced not only by temporal constraints but also by task-intrinsic factors such as task distance, with the observed effects appearing independent and consistent with a two-factor framework.

Ventral tegmental area neurons participate in reward learning, motivation, and movement but also have an emerging role in the regulation of aversive behaviors. While these diverse contributions have been attributed to distinct projections of ventral tegmental area neurons, it remains unresolved how these neurons inherit their array of behavioral functions. The ventral tegmental area is rich with acetylcholine receptors and receives dense cholinergic input from the mesopontine tegmentum. While it is known that acetylcholine release in the ventral tegmental area can increase dopamine output we lack an understanding of the scenarios which necessitate ventral tegmental area acetylcholine release. We sought to provide a comprehensive overview of the participation of ventral tegmental area acetylcholine signaling across valence to motivated behavior. Rats were trained on a diverse array of tasks that allowed for the isolation of the contribution of acetylcholine release in the ventral tegmental area to cue- and context-driven behavior. We used intracranial pharmacology to determine the receptor mechanisms that contribute to acetylcholines effects. Ultimately, we found that acetylcholine release in the ventral tegmental area is necessary for appetitive and aversive states to become motivationally relevant and spur reward-seeking and threat-avoidance. We propose that this state-dependent contribution allows ventral tegmental area acetylcholine to act as a motivational gate for behavior across valence. This work expands our view of the interaction between neuromodulatory systems in the brain and opens new directions to the understanding of ventral tegmental area neurons in health and disease.

It is widely believed that starvation favours the processing of food-related cues, a notion here called the adaptive specificity hypothesis. Indeed, in Drosophila melanogaster starvation is required for appetitive odour-sugar but not for aversive odour-shock memory. Results from Gruber et al. (2013) and Meschi et al. (2024), however, suggest that starvation improves aversive short-term memory, too, challenging this hypothesis. We survey how starvation affects Drosophila associative olfactory short-term memory across 26 learning tasks. These tasks differ in the reinforcers and the amount of training, the life stage of the animals, in the predictive structure and associative timing of the task, in whether memory is expressed as an increase or decrease in odour preference, and in whether the learned behaviour is motivated by obtaining reward or avoiding/ escaping punishment. In adult flies, an improvement was observed for appetitive odour-sugar memories, whereas all tasks yielding aversive memory were unaffected. Strikingly, appetitive tasks that are not sugar-related, namely odour-shock extinction learning and punishment-relief associations, were either unaffected or even impaired, supporting the adaptive specificity hypothesis. In contrast, in 5-day-old larvae sugar-related appetitive associations were compromised, and the same was observed, to varying degrees, in larvae starved one day earlier and for aversive quinine associations, challenging the adaptive specificity hypothesis. Furthermore, we observed starvation-induced changes in locomotion and preference for a subset of the cues used in our study. Our results defy a simplistic interpretation in terms of the adaptive specificity hypothesis and call for case-by-case analyses of how starvation affects learning and behaviour.

The medial prefrontal cortex (mPFC) plays a significant role in modulating the threat response, particularly in ambiguous circumstances. The mPFC performs this role through its connectivity with multiple brain regions, including the amygdala, long regarded as the central hub for threat responses. However, the roles of specific prefrontal projections to the amygdala in contextual threat discrimination are not yet fully understood, particularly regarding more complex learning tasks and when disentangling the functionally distinct prelimbic (PL) subunit of the mPFC. Here, we challenged mice with a contextual differential threat conditioning (DTC) learning task in which subjects were repeatedly exposed to one context predictive of a foot shock (CS+) and to a similar yet distinct context that was not (CS-). While control mice showed a similar threat response in both contexts immediately after threat conditioning, within a few days of contextual exposures, controls acquire threat discrimination and freeze less to CS- than to CS+ during late DTC. However, we found that inducing localized hypofunction of neuroplasticity in PL neurons projecting to the basolateral amygdala (BLA) impairs performance on DTC. This finding identifies the specific population of neurons in PL cortices as a critical site for learning to discriminate threat.

Memory interference occurs when an older memory competes with a newer memory that shares similar features 1. The hippocampal-entorhinal system is essential for memory 2,3, and the entorhinal cortex has been implicated in interference using the latent inhibition paradigm 4. In latent inhibition, prior non-reinforced exposure to a stimulus reduces the conditioned response later elicited when that same stimulus is paired with an aversive or appetitive outcome 5. Competition-based models propose that latent inhibition arises because the memory that the pre-exposed stimulus was inconsequential competes during retrieval with the memory that the same stimulus predicts an unconditioned stimulus 6. Although entorhinal cortex lesions or inactivation impair latent inhibition 7-10, the specific contribution of the lateral entorhinal cortex (LEC) remains unclear. The LEC provides non-spatial and cue-related input to the hippocampus 11 and has been implicated in associative memory 12,13. LEC function also declines with age 14,15, a period when memory interference increases 16. Here, we used chemogenetics to transiently inhibit excitatory neurons in the LEC during retrieval in a latent inhibition paradigm. LEC inhibition did not impair conditioned fear responses to a non-pre-exposed tone, indicating that retrieval of the tone-shock association remained intact. However, LEC inhibition attenuated latent inhibition by increasing conditioned fear responses to a pre-exposed tone. Together, these findings suggest that the LEC supports retrieval of prior inconsequential stimulus memories that compete with newer conditioned associations, providing a potential mechanism by which age-related LEC dysfunction may contribute to increased memory interference. HighlightsO_LIPre-exposure to a tone attenuates retrieval of a tone-evoked conditioned fear response, revealing latent inhibition C_LIO_LILateral entorhinal cortex inhibition does not impair fear-memory retrieval in non-pre-exposed animals C_LIO_LIThe lateral entorhinal cortex is required for the expression of latent inhibition during retrieval C_LIO_LIThe lateral entorhinal cortex contributes to memory interference during retrieval of stimuli with conflicting associations C_LI In BriefGhazy et al. show that the lateral entorhinal cortex (LEC) is required for latent inhibition during retrieval, in which prior tone exposure attenuates later fear responding to that same tone. Because LEC inhibition does not impair tone-evoked conditioned fear responding, these findings indicate that the LEC contributes to memory interference when the same stimulus has conflicting associations.

Newly acquired memories are initially fragile and are consolidated into long-term memory over time. Although consolidated memories were once thought to be resistant to interference, accumulating evidence shows that memory reactivation renders them transiently labile, making them susceptible to modification or interference before reconsolidation. Crucially, however, there is substantial variation in whether reactivated memories are disrupted by new information, remain protected from it, or even strengthened by it. The factors that guide this modification are largely unknown. To systematically investigate this, we examined motor memory interference using a classic A-B-A visuomotor rotation paradigm. Participants adapted to a 30-degree clockwise rotation (A) on Day1. On Day2, an interfering 30-degree counter-clockwise rotation (B) was introduced under varied conditions: directly without reactivation, after brief reactivation of A, after expression of A without feedback, or following a gradual transition from A to B. The final experiment used explicit contextual cues (a secondary follow-through target) to distinguish A and B trials. Contrary to the simple prediction that reactivation should increase vulnerability to interference, reactivating the original memory before introducing interference protected it, as evidenced by significant savings during relearning on Day3. In contrast, introducing interference directly, without reactivation, disrupted the original memory. This protection was consistent with a contextual-inference account: the large sensory prediction error experienced during the abrupt transition from A to B served as a latent contextual cue, signaling a new context and thereby shielding the original memory from being overwritten. Eliminating this prediction error through an immediate washout session with a similar error profile or through a gradual A-to-B transition abolished the protective effect and disrupted the original memory. Furthermore, when explicit contextual cues distinguished the two perturbations, memories were protected even in the absence of a salient prediction error. Our findings are consistent with a contextual inference account in which the fate of a consolidated memory, whether it is modified or protected, is shaped by the availability of explicit cues or latent signals such as sensory prediction error at the time when interference is introduced.

Self-directed learning allows learners to actively control their learning experience and has been shown to enhance memory compared with matched yoked learning. However, it remains unclear when and how active control modulates memory-related neural activity during learning and retrieval. We recorded electroencephalography (EEG) while participants encoded objects under active and yoked learning conditions and again during a delayed recognition test approximately 24 h later. We examined event-related potential (ERP) activity across earlier processing windows, including pre-stimulus slow potentials and early N2 activity, and later processing windows, including P300, late slow-wave, and post-stimulus slow-potential activity. We also examined encoding-retrieval similarity (ERS) between neural patterns during encoding and retrieval. Behaviorally, active control improved delayed recognition, with the advantage selectively expressed in detailed recognition. In the ERP analyses, earlier processing windows showed memory-related effects, with pre-stimulus slow-potential and N2 activity differentiating subsequently remembered from forgotten items, but were not modulated by active control. By contrast, active control modulated later memory-related ERP activity, with remembered-forgotten differences expressed during late stimulus-related and immediate post-stimulus processing only in the active condition. ERS showed a similar active-control modulation: memory-related encoding-retrieval pattern similarity was evident under active learning, but not under yoked learning, with this effect involving relatively late encoding and retrieval windows. Together, these findings support a constructive-processing account, suggesting that memory formation under active control depends more strongly on rich, detailed encoding representations that can be reinstated during retrieval.

We previously reported, using in-vivo fiber photometry, that operant responding reinforced by access to a peer (social self-administration) is associated with phasic dopamine increases in nucleus accumbens (NAc) core following lever insertion (reward-availability cue) and gradual increases preceding lever-pressing. Here, we sought to replicate these findings and determine whether dopamine signals (1) generalize to responding for high-carbohydrate palatable food, (2) show opposite patterns during negative reinforcement (shock avoidance/escape), and (3) depend on whether reinforcers are experienced alone or together. We trained rats (n=11; 6 females) to lever-press for access to a same-sex peer (15 s/trial) and palatable food (45-mg pellet/trial), followed by shock avoidance/escape (0.18-0.26 mA). After training, we expressed the dopamine sensor GRAB-DA2m and implanted optic fibers into NAc core. We measured dopamine activity during sessions with either one- or three-reinforcers. During social self-administration, dopamine activity showed phasic increases following lever insertion and gradual increases preceding lever-pressing; responses were moderately greater during sessions with all three reinforcers. Palatable food self-administration showed a similar pattern, but responses were approximately twofold greater during single-reinforcer sessions. During shock avoidance/escape, dopamine activity showed phasic decreases at warning onset, lever insertion, and shock onset; responses were also greater during single-reinforcer sessions. Results suggest that NAc core dopamine signaling distinguishes positive from negative reinforcement and is modulated by reinforcer availability. Compared with single-reinforcer sessions, dopamine responses during food self-administration and shock avoidance/escape were reduced during sessions with all three reinforcers, whereas responses during social self-administration modestly increased. Significance statementNucleus accumbens (NAc) dopamine is critical for processing the valence of positive reinforcers, whereas its role in negative reinforcement is less well understood. Here, we extended our prior work on operant social self-administration to determine whether these findings generalize to food reinforcement, show the opposite pattern during operant negative reinforcement (shock avoidance/escape), and depend on whether reinforcers are experienced alone or together. Results suggest that NAc core dopamine activity differentiates positive and negative reinforcement and is modulated by the presence of other available reinforcers. Specifically, dopamine responses during food self-administration and shock avoidance/escape were reduced when all three reinforcers were available together compared with when each reinforcer was experienced alone, whereas responses during social self-administration showed the opposite pattern.

Anxiety-related traits (ARTs) have been linked to altered fear learning, but previous studies have typically examined different experimental phases and response systems, limiting the comparability of findings and the accumulation of consistent evidence. Here, we comprehensively examined associations between ARTs and fear conditioning across acquisition, extinction and renewal and across subjective, physiological and neural response systems in a well-powered sample (N = 267) using a two-day differential conditioning paradigm. ARTs were operationalized as a composite of trait anxiety, neuroticism, and intolerance of uncertainty and conditioned responding was assessed using skin conductance responses, fear-potentiated startle, US expectancy ratings, fear ratings, and functional magnetic resonance imaging. Higher ARTs were consistently associated with elevated subjective fear and US expectancy to both threat and safety cues during extinction and renewal, without corresponding elevations in physiological responding. At the same time, ARTs were not associated with threat-safety discrimination in subjective or physiological measures across phases, while neural associations were limited to reduced dorsal anterior cingulate cortex discrimination during early renewal. These findings suggest that ARTs are characterized by a CS unspecific cognitive bias toward heightened threat expectancy and evaluation rather than altered associative fear learning, highlighting the importance of distinguishing conditioned discrimination from general levels of responding across response systems.

Perceived or volitional control over a stressor is a critical determinant of resilient versus susceptible behavioral phenotypes. Activation of the lateral habenula (LHb) is required for the behavioral changes or "learned helplessness" effects that follow inescapable, but not escapable, stress. However, the relevant LHb inputs that regulate its mediation of inescapable stress outcomes are not fully elucidated. We find that ventral tegmental area (VTA) glutamatergic axons in LHb are activated by aversive stimuli, and this activation was not altered by prior inescapable stress experience. Similarly, optogenetic activation of VTA glutamatergic axons in LHb resulted in c-Fos expression in LHb neurons that did not depend on a prior inescapable stress experience. Photoinhibition of VTA glutamatergic axons in LHb during each inescapable stress trial prevented social and nonsocial consequences of inescapable stress. We interpret these results such that VTA glutamatergic inputs to LHb report aversive stimuli to LHb, possibly related to current salient aversive experience without regard to prior stress history. Nevertheless, VTA glutamatergic input to the LHb plays an important role in regulating LHb-mediated social and nonsocial consequences of uncontrollable stress.

Learning depends not only on the content of what we learn, but also on how we learn and on how experiences are structured over time. To investigate how task similarity and training regime interact during learning, we trained participants on spatial and conceptual learning tasks that shared either similar or distinct underlying structures, using either interleaved or blocked regimes. Interleaving the two tasks hindered performance when their structures were similar, compared to when they were different. In contrast, blocked training produced the opposite effect: it improved performance and facilitated transfer across similar tasks. This effect, however, emerged only when participants first learned the conceptual task, followed by the spatial task, suggesting an asymmetric interaction between task order and structural similarity. We also replicated our results using a neural network model, providing converging evidence for the computational principles governing the interplay between training regime and structural similarity in multi-task learning.

Studying chess experts helps researchers understand how intensive practice shapes thinking skills. Cognitive flexibility is the ability to adjust thoughts when rules or tasks change. Working memory is the ability to hold and use information over short periods. This study compared cognitive flexibility and working memory precision between adolescent chess players and non-players. Twenty-four professional chess players and twenty-five controls completed two novel behavioral tasks. Chess players showed better accuracy in both tasks than controls. They adapted more efficiently when rules changed during a continuous learning task. They also remembered facial expressions more precisely in a working memory task. Learning rates in the flexibility task did not differ between groups. These results indicate that chess expertise may improve rule-guided flexibility and visual working memory precision in adolescents.