The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement

The brain transforms the need for water into the desire to drink, but how this transformation is performed remains unknown. Here we describe the motivational mechanism by which the forebrain thirst circuit drives drinking. We show that thirst-promoting subfornical organ neurons are negatively reinforcing and that this negative-valence signal is transmitted along projections to the organum vasculosum of the lamina terminalis (OVLT) and median preoptic nucleus (MnPO). We then identify molecularly defined cell types within the OVLT and MnPO that are activated by fluid imbalance and show that stimulation of these neurons is sufficient to drive drinking, cardiovascular responses, and negative reinforcement. Finally, we demonstrate that the thirst signal exits these regions through at least three parallel pathways and show that these projections dissociate the cardiovascular and behavioral responses to fluid imbalance. These findings reveal a distributed thirst circuit that motivates drinking by the common mechanism of drive reduction. •The genes Agtr1a and Adcyap1 label thirst neurons in the OVLT and MnPO, respectively•SFO, OVLT, and MnPO thirst neurons control both drinking and blood pressure•Stimulation of thirst neurons in SFO, OVLT, and MnPO is negatively reinforcing•MnPO projections dissociate the cardiovascular and behavioral outputs of the LT Leib et al. reveal the motivational mechanism by which the thirst circuit drives drinking. They show that molecularly defined cell types in three forebrain nuclei promote drinking by drive reduction and also coordinate the cardiovascular response to fluid imbalance.