Substance P regulates Tacr1 neurons, which control nitric oxide-mediated neurovascular coupling in the mouse cortex.

Abstract

Neuronal activity-driven increases in cerebral blood flow (CBF), known as neurovascular coupling (NVC), are crucial for sustaining the metabolic demands of the brain. Our group has found that Tacr1 neurons, a subset of somatostatin neurons expressing the substance P (SP) receptor and neuronal nitric oxide synthase (nNOS), exert a disproportionately large regulation of CBF. Here, we use two-photon imaging to show that Tacr1 neurons regulate CBF through nitric oxide (NO) release and SP-receptor signaling . We identify astrocytic calcium (Ca²⁺) transients as a secondary response to vasodilation. To identify potential sources of SP in somatosensory cortex, viral mapping revealed <i>Tac1</i>-positive neurons locally, predominantly among parvalbumin (PV) neurons, as well as <i>Tac1</i>-positive long-range projections from perirhinal cortex. Functional analyses indicate that PV neurons regulate CBF through a Tacr1 neuron dependent pathway. These findings suggest a sequential mechanism whereby Tacr1 neurons respond to SP to release NO, inducing vasodilation and driving astrocytic Ca²⁺ signaling.