To test the hypothesis that opiates reinforce self-administration through modulation of memory consolidation, three experiments in male Sprague-Dawley rats explored whether post-training heroin administration could facilitate drug place conditioning and escape learning in the Barnes maze. Immediately following heroin- (1 mg/kg; Experiment 1) or cocaine-compartment (20 mg/kg; Experiment 2) conditioning sessions, rats received vehicle, 1 mg/kg heroin, or 1 mg/kg heroin in combination with 3 mg/kg naloxone. All groups were tested after one pairing (Test 1) and again after three additional pairings (Test 2). Experiment 3 assessed the effects of vehicle, 1 and 2 mg/kg heroin administered immediately following each of 10 escape training sessions. All groups were tested drug-free on a final Probe test when the escape location was moved to the opposite quadrant of the maze. Contrary to predictions, in both place conditioning experiments there was no significant drug-compartment preference in rats that received post-training 1 mg/kg heroin, and this effect was reversed by naloxone. In the Barnes maze, post-training 1 mg/kg heroin did enhance investigation of the escape location during training. However, during the Probe test, 1 mg/kg increased while 2 mg/kg decreased investigation of the original escape location, and only 1 mg/kg enhanced locomotion within the original training quadrant. Taken together, this complex pattern of results cannot be interpreted simply from a memory consolidation perspective and suggests that, even when administered post-training, heroin can influence subsequent task performance through incidental learning.

It is becoming increasingly clear that chronic exposure to lower levels of ethanol impacts learning and behavior. To determine the effect of chronic low-dose ethanol exposure on sensitivity to changes in stimulus value, a conditioned taste aversion procedure was used. Adult male and female mice underwent a sucrose two bottle-choice drinking paradigm. Each day, mice received an injection of either low-dose ethanol (0.5 g/kg) or saline 1 h after sucrose access for 20 days. This was followed by a lithium chloride (LiCl)-induced conditioned taste aversion (CTA) paradigm in which 0.15M LiCl or vehicle injection was administered immediately after sucrose consumption for three days. On the fourth day, changes in sucrose consumption were analyzed. Chronic exposure to low-dose ethanol did not affect sucrose consumption in either female or male mice during two-bottle choice. In female mice, a history of chronic low-dose ethanol exposure blocked the development of LiCl-induced CTA. A history of chronic low-dose ethanol did not impact LiCl-induced CTA in male mice as both ethanol-naive and -exposed male mice who underwent LiCl pairing reduced sucrose consumption. This suggests that low-dose ethanol altered aversion-related behavior in female mice, which may have implications for development of aberrant reward seeking.

Learning about danger through exposure to harmful events relies on Pavlovian conditioning, which enables individuals to prepare for potential threats when encountering warning signals in the future. Sensory preconditioning further shows that defensive significance can extend to neutral cues associated with a subsequently conditioned stimulus, even when those cues have never themselves been paired with an aversive outcome. Here, we asked whether this principle extends to a relational memory structure assembled across separate neutral experiences, and whether cues closer to the conditioned threat cue within this structure evoke stronger defensive responses. Participants first learned overlapping pairs of neutral images that together formed an abstract linear graph. The following day, the two images at opposite ends of the graph were differentially paired with mild electric shocks, establishing them as threat and safety signals. When later exposed to the remaining images under risk of shock, participants exhibited graded defensive responses across self-report and physiological measures that varied systematically with relational distance from the conditioned cues. These findings extend the principle of sensory preconditioning from elementary arrangements to a multistep relational memory structure, showing that the organization of prior neutral memories can shape the graded expression of defensive responses.

Memory generalization allows individuals to extract and apply information from prior experiences to novel situations, supporting flexible learning and efficient decision-making. Theoretical models suggest that sleep should facilitate generalization, yet the literature examining its role in promoting generalization is mixed. We recruited 137 participants via Prolific to complete an image-location memory task over two sessions spaced 12 h apart. Participants were randomly assigned to the Wake group (learning in the morning) or the Sleep group (learning in the evening). In Session 1, participants learned the location of stimuli on the screen and were tested on their memory 5 min later. Twelve hours later, in Session 2, they were tested on their memory again. Stimuli consisted of 160 images from eight semantic categories and were strategically positioned on-screen to test the effects of generalization on retrieval (i.e., category-based memory distortions and biases). After the delay, retrieval was less accurate and demonstrated more generalization. However, these effects were mostly independent of Group, with some evidence for enhanced generalization following a period of wakefulness over sleep. Generalization was also driven by time of day, with more generalization in the evening relative to the morning. Taken together, our results, based on a large online sample, do not support a role for sleep in promoting memory generalization.

Fragile X syndrome (FXS) is a leading inherited cause of intellectual disability. FXS is caused by a trinucleotide repeat expansion in the fragile X messenger ribonucleoprotein 1 (fmr1) gene, which results in transcriptional silencing, and loss of its protein product, FMRP. One symptom of FXS is cognitive inflexibility, but there is no generally accepted way to test this in rodents. Tests of reversal learning or extinction paradigms have been used as measures of cognitive flexibility, but these are indirect, require substantial training and experimenter effort, and often yield inconsistent results. This study tests male and female Fmr1 knockout (KO) and wild-type (WT) mice in a "puzzle box" specifically designed to assess cognitive flexibility. The Puzzle Box is a two-chambered apparatus with a brightly illuminated area and an enclosed goal area. Novel obstacles block the underpass to the goal area, requiring that mice adopt new strategies. Results reveal that female, but not male, Fmr1 KO mice exhibit impaired performance compared to WT controls. Analysis of behavioral measures during novel obstacle presentation revealed a behavioral phenotype consistent with increased anxiety-like and hyperactivity behaviors, as well as altered engagement with novel obstacle conditions, in female Fmr1 KO mice compared to WT controls. Overall, the Puzzle Box test shows promise as a rapid screening test for cognitive flexibility impairments in FXS or other rodent models of neurological disorders.

Computational models and neurobehavioral data suggest that encoding variability affects forced-choice mnemonic discrimination. Here, we experimentally manipulated encoding variability on the forced-choice Mnemonic Similarity Task by varying stimulus repetitions during encoding. We first generated predictions from a global matching model. Behavioral data supported all predictions. Across most conditions, repetitions consistently enhanced mnemonic discrimination; however, when encoding variability was induced by 3-repetitions of the original version of the noncorresponding lure and 1-repetition of the target during learning, individuals exhibited increased interference. These findings provide further insight into theories of human memory, especially the effect of stimulus repetition on mnemonic discrimination.

Memory cues can be associated with both positive and negative experiences at different time points, in either a positive-to-negative or negative-to-positive order. While sleep preferentially consolidates recent experiences, its impact on emotional memory across such opposing-valence sequences remains unclear. We tested whether sleep differentially modulates delayed cue affect in positive-to-negative versus negative-to-positive conditions. One hundred twenty participants were randomly assigned to sleep or wake groups and completed both conditions in counterbalanced order. Participants learned pseudoword-picture associations where the same cues were paired with emotional pictures of opposite valence. Emotional valence ratings were collected immediately after encoding and after a 12 h interval (overnight sleep vs. daytime wakefulness). Sleep led to more positive cue ratings in the negative-to-positive condition and more negative ratings in the positive-to-negative condition, compared to wake controls. Stronger positive picture ratings predicted greater positive-valence shifts after sleep in the negative-to-positive condition. These findings indicate that sleep preferentially modulates the affective tone of memories encoded closer to sleep onset, independent of recognition accuracy. This suggests a dissociation between mnemonic and affective consolidation, where sleep selectively biases emotional value according to the temporal order of experience. This principle may inform therapeutic strategies for optimizing emotional outcomes by timing positive experiences before sleep, though clinical applications require further study.

Murine studies show that the gut microbiota-the collection of the microbes residing in the large intestine-affects memory performance in the host. However, whether commensal gut bacteria are linked to human episodic memory remains unknown. Here, we investigated whether individual differences in episodic memory performance were associated with differences in the indigenous gut microbiota composition between individuals. We show that greater gut microbiota α diversity was associated with better item recognition and that gut microbiota dissimilarity index (β diversity) between participants was associated with differences in their performance. Finally, our results suggest that Prevotella copri might play a role in the relationship between gut microbiota and human item recognition in healthy individuals. In a sample size larger than previous human studies and examining unmanipulated gut microbiota, we provide evidence that episodic memory in healthy humans is linked to their gut microbiota composition.

Memory updating requires detecting changes between similar events and preserving information about their relative order. Two experiments examined whether memory-based rejection of similar lures in the Mnemonic Similarity Task supports subsequent temporal memory. Participants studied objects, completed a modified recognition test including repeated targets, similar lures, and novel foils, and then performed a relative recency test in which they selected which of two versions of the same object appeared during the previous recognition test. Recency judgments for lures were most accurate when they were correctly rejected as "similar," suggesting that retrieval-based comparison processes during recognition supported subsequent memory updating. Conditional analyses showed that this benefit was enhanced when participants also reported the subjective experience of remembering that both objects had appeared in the experiment, indexing memory for change. Subjective reports of retrieving studied objects before seeing lures were associated with more accurate lure decisions, and clearer subjective retrieval was associated with more frequent reports indicating memory for change. Together, these findings suggest that retrieval and comparison processes engaged during mnemonic discrimination encode information that supports distinguishing earlier and later events. This study provides a step toward integrating cognitive accounts of temporal memory with complementary neural accounts of episodic memory updating.

Chronic stress is a major risk factor for psychiatric disorders. Previous work from our laboratory has demonstrated that chronic stress exposure disrupted network activity in the basolateral amygdala (BLA) and altered the activity of projection-specific neurons in the BLA to bias information processing to favor negative valence processing. Although the BLA is well established as a critical hub for fear memory encoding and retrieval, it remains unclear how chronic stress alters ensemble recruitment within the BLA and its downstream circuit dynamics to shape fear and extinction learning. To answer this question, we used retrograde tracing combined with immunohistochemistry in adult male mice to examine how chronic unpredictable stress (CUS) during adulthood alters the activity of the BLA and its projections to the nucleus accumbens (NAc) or bed nucleus of the (BNST) following fear extinction. Here we demonstrate that CUS produced a shift toward persistent threat responding and alters extinction learning, accompanied by reduced recruitment within the lateral nucleus of the BLA (LA) and in BLA-NAc projecting neurons. These findings provide circuit-level evidence for how chronic stress disrupts information flow from BLA, biasing valence processing toward extinction-resistant fear states and potentially contributing to the persistence of maladaptive fear in stress-related psychiatric disorders.

Strong evidence has emerged over the last two decades implicating proteasome-dependent and independent protein polyubiquitination in the memory consolidation process. Recently, it was shown that multiple forms of polyubiquitination, including proteasome-dependent K48 and proteasome-independent M1 polyubiquitination, regulate fear memory formation in a sex-dependent manner in the amygdala. However, prior work focused on single time points during the postlearning period, leaving questions about whether these are true sex differences in polyubiquitin modifications that persist throughout the extended consolidation process. Here, using unbiased polyubiquitin-type specific proteomics, we identified the protein targets of K48 and M1 polyubiquitination in the amygdala 2 and 4 h after contextual fear conditioning. Notably, we found that while the sex differences in the targeting of proteins with these polyubiquitin modifications persist for several hours after fear conditioning, the temporal dynamics of these changes vary across males and females. Further, while target protein pathways vary significantly across sexes at every time point examined, there are several notable overlaps between males and females. Together, these data provide the first comprehensive analysis of sex differences in proteasome-dependent and independent protein polyubiquitination in fear memory formation and significantly advance our understanding of the potential sex-specific roles of diverse polyubiquitin modifications in the memory consolidation process.

Flexible strategy use relies on the concerted effort of multiple cognitive processes. Originally appreciated for its role in aversive conditioning (for review, see Mondoloni et al., Transl Psychiatry 12: 86 [2022]), the lateral habenula (LHb) has recently been linked to flexible behavior more broadly (Baker et al., Front Behav Neurosci 9: 1-22 [2015]; Baker et al., Front Mol Neurosci 12: 1-15 [2019]; Mizumori and Baker, Trends Neurosci 40: 481-493 [2017]; Hones and Mizumori, Front Behav Neurosci 16: 852235 [2022]; Ahmadlou et al., Nature 641: 151-161 [2025]), prompting the question as to whether its encoding of negative outcomes contributes specifically to adaptive strategy switching. To address this gap in knowledge, the present study investigated how LHb inactivation with muscimol affects distinct aspects of flexible decision-making that depend on an understanding of negative outcomes when using a spatial set-shifting task. LHb inactivation resulted in a decreased ability to efficiently acquire new strategies after changes in reward contingencies but did not affect the exploitation of adopted strategies. A measure of choice flexibility confirmed that, without an intact LHb, rats fail to appropriately adapt to new strategies following errors. This effect suggests that the LHb contributes to the appropriate use of negative choice outcomes to inform future decisions. Therefore, aversive signaling in the LHb may play a broad role beyond purely aversive contexts, such as in guiding behavioral adaptation.

Episodic memory helps facilitate navigation of the social world. Yet, whether social content is prioritized in episodic memory is unclear. Testing whether social elements are prioritized when retrieving multielement episodes used for social and nonsocial inferences, online volunteers encoded episode triplets comprising a location, activity, and a clique (i.e., social group) that related to a cue that was either a person or an object. Subsequent associative memory tests in all tasks revealed some form of enhanced retrieval for activity pairings with cliques. Additionally, social cover task contexts further boosted retrieval of social event content linked to the same cue. Computational modeling of retrieval response times revealed that these effects were consistent with more holistic retrieval of event triplets when retrieving social content. These results imply that social content can hold a privileged role over other event details in episodic memory, while offering a putative mechanism for social prioritization in episodic memory processes.

It is not yet clear how dorsal hippocampal rhythms contribute specific information that impacts future behavior. Using a spatial set-shifting task that requires animals to behave flexibly and continuously adapt to different spatial strategies, we found that beta power increased after incorrect choices. Higher beta and gamma power after reward feedback was linked with greater accuracy on the next trial, scaling with rhythm power. These results highlight the importance of relating hippocampal rhythms to multiple within-trial segments to better understand how individual rhythms may differentially support future behaviors.