Summary Thermoregulation is one of the most vital functions of the brain, but how temperature information is converted into homeostatic responses remains unknown. Here we use an unbiased approach for activity-dependent RNA sequencing to identify warm-sensitive neurons (WSNs) within the preoptic hypothalamus that orchestrate the homeostatic response to heat. We show that these WSNs are molecularly-defined by co-expression of the neuropeptides BDNF and PACAP. Optical recordings in awake, behaving mice reveal that these neurons are selectively activated by environmental warmth. Optogenetic excitation of WSNs triggers rapid hypothermia, mediated by reciprocal changes in heat production and loss, as well as dramatic cold-seeking behavior. Projection-specific manipulations demonstrate that these distinct effectors are controlled by anatomically segregated pathways. These findings reveal a molecularly-defined cell type that coordinates the diverse behavioral and autonomic responses to heat. Identification of these warm-sensitive cells provides genetic access to the core neural circuit regulating the body temperature of mammals.

Thirst motivates animals to drink in order to maintain fluid balance. Traditionally, thirst has been viewed as a homeostatic response to changes in the blood volume or tonicity1–3. However, most drinking behavior is regulated too rapidly to be controlled by blood composition directly and instead appears to anticipate homeostatic imbalances before they arise4–11. How this is achieved remains unknown. Here we reveal an unexpected role for the subfornical organ (SFO) in the anticipatory regulation of thirst. We show by monitoring deep-brain calcium dynamics that thirst-promoting SFO neurons respond to inputs from the oral cavity during eating and drinking, which they then integrate with information about the composition of the blood. This integration allows SFO neurons to predict how ongoing food and water consumption will alter fluid balance in the future and then adjust behavior preemptively. Complementary optogenetic manipulations show that this anticipatory modulation is necessary for drinking in multiple contexts. These findings provide a neural mechanism to explain longstanding behavioral observations, including the prevalence of drinking during meals10,11, the rapid satiation of thirst7–9, and the fact that oral cooling is thirst-quenching12–14.

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