Wiring and Molecular Features of Prefrontal Ensembles Representing Distinct Experiences

A major challenge in understanding the cellular diversity of the brain has been linking activity during behavior with standard cellular typology. For example, it has not been possible to determine whether principal neurons in prefrontal cortex active during distinct experiences represent separable cell types, and it is not known whether these differentially active cells exert distinct causal influences on behavior. Here, we develop quantitative hydrogel-based technologies to connect activity in cells reporting on behavioral experience with measures for both brain-wide wiring and molecular phenotype. We find that positive and negative-valence experiences in prefrontal cortex are represented by cell populations that differ in their causal impact on behavior, long-range wiring, and gene expression profiles, with the major discriminant being expression of the adaptation-linked gene NPAS4. These findings illuminate cellular logic of prefrontal cortex information processing and natural adaptive behavior and may point the way to cell-type-specific understanding and treatment of disease-associated states. [Display omitted] •Cohort-scale CLARITY is enabled for whole-brain activity/projection measurements•mPFC cells active during distinct-valence experiences exhibit distinct projections•Positive-valence experience preferentially recruits an NPAS4+ population in mPFC•Recruiting diverse experience-defined mPFC ensembles drives distinct behaviors A quantitative analysis of the wiring and molecular properties of neurons in the prefrontal cortex that are associated with distinct behavioral experiences illuminates the logic of information processing in the brain.