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

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 (Ca 2+ ) transients as a secondary response to vasodilation. To identify potential sources of SP in somatosensory cortex, viral mapping revealed Tac1 -positive neurons locally, predominantly among parvalbumin (PV) neurons, as well as Tac1 -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 Ca 2+ signaling.