The Thirsty Brain: Integrating Molecular Signals, Neural Circuit, and Behavior

For most organisms, drinking behavior is essential for maintaining fluid homeostasis and fundamental to survival and normal physiological functions. Physiologically motivated drinking is typically triggered by thirst, which originates from the brain's perception and processing of signals reflecting changes in osmotic pressure, blood volume, and psychological factors. This behavior is mainly regulated by neural circuits centered on the lamina terminalis and hormonal signals such as angiotensin II and arginine vasopressin, collectively ensuring precise control of fluid homeostasis. In this review, we systematically discuss the multisystemic mechanisms underlying thirst generation, the integration from motivation initiation, and execution to behavioral termination of drinking and summarize the molecular mechanisms of thirst-related neuronal populations in several brain regions, along with the specific regulatory roles of their neural circuits. Additionally, we discuss the long-range communication between peripheral organs and the central nervous system in thirst modulation, as well as the fluctuations and impacts of fluid-regulating hormones under different homeostatic conditions. Finally, we highlight several unresolved research gaps in current knowledge and discuss perspectives for future investigation and potential clinical translation.