Ventricular Expansion Couples Hyperosmotic Stress to Thirst

Thirst is thought to arise from osmotic signals detected by circumventricular organs, yet how hyperosmotic stress activates mechanosensitive channels remains unclear because cell shrinkage should reduce membrane tension. Here we identify a brain-scale mechanical signal that couples systemic osmotic stress to drinking. In mice, hypertonic saline rapidly increased serum and cerebrospinal fluid osmolality, expanded the lateral ventricles, and promoted water intake. Relieving or blocking ventricular deformation attenuated drinking without eliminating osmotic gradients. Hyperosmotic challenge also produced localized deformation of periventricular cells, where spatial transcriptomics revealed candidate mechanosensitive channels, including Tmem63b and Piezo1. Thus, ventricular expansion provides a mechanical component of osmotic thirst, uncovering an osmo-mechanical layer of interoceptive regulation.