The Forebrain Thirst Circuit Drives Drinking through Negative Reinforcement

Abstract

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.

From sensory circumventricular organs to cerebral cortex: Neural pathways controlling thirst and hunger

“…37 In this regard, light-activation of the dipsogenic MnPO to lateral hypothalamic area pathway, but not the dipsogenic MnPO to PVT pathway, causes mice to lever-press to stop the photostimulation or avoid the place where it is triggered. 38 These data are consistent with the idea that different neural paths projecting from the lamina terminalis may mediate the various subjective components of thirst.…”

“…27,28 Although ablation of the subfornical organ did not impair drinking responses to systemic infusion of hypertonic saline in rats and sheep, 7,29 if it was ablated together with the OVLT in sheep, drinking to this stimulus was impaired compared to animals in which the OVLT alone was ablated. [36][37][38][39] Furthermore, recent experiments in mice show that optogenetic stimulation of osmoresponsive neurones in the subfornical organ or OVLT (as indicated by their expression of c-Fos in response to hypertonicity or dehydration), immediately begin to drink water. These neurones express several genes that include neuronal nitric oxide synthase (nNOS), Ca/calmodulin-dependent protein kinase II, the transcription factor ETS translocation variant-1 and the angiotensin AT 1a receptor.…”

“…In addition, they are excitatory glutamatergic neurones because they express the glutamate transporter Vglut2. [36][37][38][39] Furthermore, recent experiments in mice show that optogenetic stimulation of osmoresponsive neurones in the subfornical organ or OVLT (as indicated by their expression of c-Fos in response to hypertonicity or dehydration), immediately begin to drink water. 37 Thus, subfornical organ and OVLT neurones expressing nNOS/Glut2 (hereafter referred to as SFO Glut and OVLT Glut , respectively) appear to be the origin of neural signals that drive osmotic and hormonally mediated thirst.…”

“…when the channel-rhodopsin within their terminals in the MnPO is stimulated by light, drinking occurs immediately 14,38. Furthermore, when such MnPO neurones that receive input from SFO Glut neurones are genetically modified to express caspase3, thereby resulting in their ablation, water drinking caused by stimulation of SFO Glut or glutamatergic neurones within OVLT (OVLT Glut ) is greatly reduced,56 as is drinking caused by dehydration 56.…”

Thirst regulates motivated behavior through modulation of brainwide neural population dynamics

“…The activity of glutamatergic hypothalamic thirst-related neurons establishes a persistent, aversive motivational drive that animals can reduce in real time by consuming water (19, 20). The brainwide activity mode we identify appears to represent the direct effects of this thirst neuron activity that is broadcast to downstream circuits.…”