Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles

What is the contribution of molecularly defined cell types to neural coding of stimuli and states? Xu et al. aimed to evaluate neural representation of multiple behavioral states in the mouse paraventricular hypothalamus. To achieve this goal, they combined deep-brain two-photon imaging with post hoc validation of gene expression in the imaged cells. The behavioral states could be well predicted by the neural response of multiple neuronal clusters. Some clusters were broadly tuned and contributed strongly to the decoding of multiple behavioral states, whereas others were more specifically tuned to certain behaviors or specific time windows of a behavioral state. Science , this issue p. eabb2494 An imaging method can merge molecular and systems neuroscience to reveal combinatorial cell type coding of essential survival behaviors. Brains encode behaviors using neurons amenable to systematic classification by gene expression. The contribution of molecular identity to neural coding is not understood because of the challenges involved with measuring neural dynamics and molecular information from the same cells. We developed CaRMA (calcium and RNA multiplexed activity) imaging based on recording in vivo single-neuron calcium dynamics followed by gene expression analysis. We simultaneously monitored activity in hundreds of neurons in mouse paraventricular hypothalamus (PVH). Combinations of cell-type marker genes had predictive power for neuronal responses across 11 behavioral states. The PVH uses combinatorial assemblies of molecularly defined neuron populations for grouped-ensemble coding of survival behaviors. The neuropeptide receptor neuropeptide Y receptor type 1 (Npy1r) amalgamated multiple cell types with similar responses. Our results show that molecularly defined neurons are important processing units for brain function.