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.
The Morris Water Task (MWT) has been the gold standard assessment of place learning and memory for over four decades, yet the processes that contribute to successful navigation are not completely understood. It is generally posited that rats learn to navigate directly to a place; however, navigation is not perfectly direct but contains variation in swim speed and trajectory resulting in efficient, yet suboptimal paths. Gonçalves-Garcia et al. (2024) demonstrated that path topography is quantitatively similar across trials within individual rats for a given start location, and dissimilar between rats and different start locations within rat. This suggests rats may take unique paths to the platform from each release point. If such variation reflects learned behavior, it should be possible to objectively classify (identify) individual rats using machine learning. In the present study, a recurrent neural network was trained to classify 15 rats based on trial-level time-series data of path coordinates, velocity, and orientation. Testing on unseen coordinates or combined features from the same starting locations yielded classification accuracies that were 5.93-7.26-fold greater than chance and significantly greater than data from different start locations. Classification using scalar metrics with support vector machines was unable to match these outcomes. Collectively, these observations support the hypothesis that navigation in the MWT involves learning to perform behavioral sequences.
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.
