Figure 2. Anticipatory and homeostatic regulation of the thirst circuit.

a | Challenges to fluid homeostasis, such as water deprivation, cause deviations in the composition of the blood. These deviations can include increases in plasma osmolality (P_osmolality) and sodium (P_Na), as well as decreases in plasma volume (P_volume) and pressure that stimulate renin secretion by the kidneys and, consequently, AngII production (P_AngII) in the blood¹³⁷. These homeostatic circulating signals are translated by the brain into counter-regulatory responses, including thirst, anorexia, vasopressin (P_AVP) and oxytocin (P_OXT) secretion, and sympathetic nerve activation (SNA). While thirst is ultimately necessary to restore fluid homeostasis, this coordinated set of responses also promotes water retention (antidiuresis) and sodium excretion (natriuresis) by the kidneys, suppresses ingestion of food (and, therefore, sodium and other osmolytes), and modulates blood pressure and heart rate in order to maintain fluid homeostasis until water can be ingested. b | When thirsty animals are allowed to drink (red area), thirst and AVP secretion (blue lines) are rapidly inhibited before the composition of the blood (green lines) is corrected by ingested water. Historical experiments using esophageal/gastric fistulae and sham drinking suggest that this anticipatory regulation involves both immediate oropharyngeal and delayed visceral signals, however the neural mechanism underlying rapid anticipatory regulation of thirst and AVP secretion remained unexplored until recently. c | Fiber photometry recordings revealed that SFO^GLUT neurons are rapidly inhibited during drinking to coordinate the anticipatory control of thirst and AVP secretion¹⁶. In this example recording, a thirsty mouse (48 h water restriction) is given access to water. The inset highlights that rapid inhibition of SFO^GLUT neurons is time-locked to individual drinking bouts (red areas). d | Fiber photometry recordings confirmed that SON^AVP neurons are also rapidly inhibited during drinking¹⁹. In this example recording, a thirsty mouse (24 h water restriction) is given access to water. The inset highlights that SON^AVP neurons are transiently inhibited by water-predicting cues before drinking is initiated and that this inhibition is rapidly reset in the seconds immediately prior to water ingestion. The neural mechanism and physiological significance of this transient pre-ingestive inhibition remain unclear. e | In addition to homeostatic circulating signals (e.g., P_osmolality, P_Na, and P_AngII) that were canonically thought to activate the LT (see Panel a), recent experiments have revealed that a diverse set of anticipatory oropharyngeal, visceral, and circadian signals also influence SFO^GLUT neurons and the LT on different time-scales. This convergence of homeostatic and anticipatory signals allows SFO^GLUT neurons and the LT to control a diverse set of behavioral, neuroendocrine, and autonomic outputs both in response to and in anticipation of deviations from fluid homeostasis. Data in Panel 2c is adapted from ref. 16. Data in Panel 2d is adapted from ref. 19.