Secretin drives thirst by activating glutamatergic neurons in the subfornical organ

Abstract

Animals instinctively find and consume water when feeling thirsty and thereby restore body fluid osmolality and plasma volume to their set points. This mechanism is accomplished by regulating the cardiovascular system, endocrine system, and central and peripheral nervous systems. In mammals, thirst and salt appetite are strongly influenced by the subfornical organ (SFO) and median preoptic nucleus (MnPO), two anatomically interconnected lamina terminalis (LT) in the forebrain. The SFO lies outside the blood-brain barrier and contains neurons that directly monitor circulation to sense changes in plasma osmolality, blood pressure, and hormones [e.g., angiotensin II (Ang II)] during fluid imbalance and utilize this information to generate thirst and/or salt appetite. MnPO, on the other hand, cannot directly receive signals from circulation but integrates SFO inputs to restore fluid balance. Given its indispensable role in maintaining body fluid homeostasis, the LT is the logical starting point for the motivation of thirst. Glutamatergic neurons in SFO/MnPO that express neuronal nitric oxide synthase (SFO/MnPOnNOS neurons) are strongly activated under dehydration, and optogenetic activation of these neurons can promote voracious water intake even under hydrated conditions. On the other hand, GABAergic neurons in SFO/MnPO are rapidly activated upon water ingestion to quench thirst. These studies indicate that the neural substrates in the LT exhibit both temporal and spatial distinctions in regulating drinking behavior.

Secretin (SCT), a classic gastrointestinal hormone, was recently identified as a key factor that regulates body fluid homeostasis. Both intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration of SCT significantly triggered water intake in rodents. SCT is present throughout the hypothalamo–neurohypophysial axis and is implicated to be released to peripheral circulation under hyperosmolality. Interestingly, an intact SCT-SCT receptor (SCTR) axis was shown to be critical for the osmoregulatory activities of Ang II, as i.c.v.-Ang II in Sct-/- and Sctr-/- mice did not induce a typical increase in water intake and vasopressin release. Notably, SCT and SCTR are also expressed in the SFO, suggesting that they may be directly involved in body fluid balance dominated by SFO. These data indicate that SCT is a dipsogenic factor, but the neural basis of its action is unclear. Here, we show that the site-specific ablation of either SCT or SCTR in the SFO reduces water but not salt intake in dehydrated mice, and this effect could be completely rescued by exogenous SCT administration. Using a series of complementary approaches, we show that the SCT-SCTR axis in the SFO is responsible for activating SFO glutamatergic neurons under water deprivation or angiotensin II treatment. Electrophysiology with single-cell reverse transcription PCR indicates that SCT directly activates SFOnNOS neurons via SCTR in a cell-autonomous manner. Furthermore, local Sctr gene ablation in the MnPO, the major downstream nucleus of SFO, reduces water intake in dehydrated mice. A projection-specific gene deletion approach also shows that SCT/SCTR in SFO→MnPO neurons is necessary for water intake under dehydration. The present study thus reveals SCT/SCTR-dependent neural mechanisms in the central nervous system to drive thirst.