A bottom-up septal inhibitory circuit mediates anticipatory control of drinking

Drinking behavior is not only homeostatically regulated but also rapidly adjusted before any changes in blood osmolality occur, known as anticipatory thirst satiation. Homeostatic and anticipatory signals converge in the subfornical organ (SFO); however, the neural pathways conveying peripheral information to the SFO before changes in blood composition are incompletely understood. Here we reveal an inhibitory pathway from the medial septum (MS) to the SFO that is involved in the control of anticipatory drinking behavior in mice. MS γ-aminobutyric acid (GABA)ergic neurons encode water-satiation signals by integrating cues from the oral cavity and tracking gastrointestinal signals. These neurons receive inputs from the parabrachial nucleus and relay to SFOCaMKII neurons, forming a bottom-up pathway with activity that prevents overhydration. Disruption of this circuit leads to excessive water intake and hyponatremia. Our findings reveal a septal pathway that integrates multiple layers of presystemic signals to fine-tune drinking behavior. Xu et al. reveal that a bottom-up neural circuit from the medial septum to the subfornical organ prevents overhydration in mice by integrating oral and gastrointestinal signals before osmolality changes, demonstrating precise drinking control mechanisms.