Many neuropsychiatric diseases are associated with cognitive rigidity linked to prefrontal dysfunction. For example, schizophrenia and Parkinson's disease are associated with performance deficits on the Wisconsin Card Sorting Test, which evaluates attentional set shifting. Although the genetic underpinnings of these disorders can be reproduced in mice, there are few models for testing the functional consequences. Here, we demonstrate that an analog of the Wisconsin Card Sorting Test, developed in marmosets and recently adapted to rats, is a behavioral model of prefrontal function in mice. Systematic analysis demonstrated that formation of the attentional set in mice is dependent on the number of problem sets. We found that mice, like rats and primates, exhibit both affective and attentional sets, and these functions are disrupted by neurotoxic damage to orbitofrontal and medial prefrontal cortical areas, respectively. These data are identical to studies in rats and similar to the deficits reported after prefrontal damage in a comparable task in marmosets. These results provide a behavioral model to assess prefrontal function in mice.

SummaryActivity in striatal direct- and indirect-pathway spiny projection neurons (SPNs) is critical for proper movement. However, little is known about the spatiotemporal organization of this activity. We investigated the spatiotemporal organization of SPN ensemble activity in mice during self-paced, natural movements using microendoscopic imaging. Activity in both pathways showed predominantly local but also some long-range correlations. Using a novel approach to cluster and quantify behaviors based on continuous accelerometer and video data, we found that SPN ensembles active during specific actions were spatially closer and more correlated overall. Furthermore, similarity between different actions corresponded to the similarity between SPN ensemble patterns, irrespective of movement speed. Consistently, the accuracy of decoding behavior from SPN ensemble patterns was directly related to the dissimilarity between behavioral clusters. These results identify a predominantly local, but not spatially compact, organization of direct- and indirect-pathway SPN activity that maps action space independently of movement speed.

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Sparse populations of neurons in the dentate gyrus (DG) of the hippocampus are causally implicated in the encoding of contextual fear memories. However, engram-specific molecular mechanisms underlying memory consolidation remain largely unknown. Here we perform unbiased RNA sequencing of DG engram neurons 24 h after contextual fear conditioning to identify transcriptome changes specific to memory consolidation. DG engram neurons exhibit a highly distinct pattern of gene expression, in which CREB-dependent transcription features prominently ( P = 6.2 × 10 −13 ), including Atf3 ( P = 2.4 × 10 −41 ), Penk ( P = 1.3 × 10 −15 ), and Kcnq3 ( P = 3.1 × 10 −12 ). Moreover, we validate the functional relevance of the RNAseq findings by establishing the causal requirement of intact CREB function specifically within the DG engram during memory consolidation, and identify a novel group of CREB target genes involved in the encoding of long-term memory.

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