BIDIRECTIONAL CONTROL OF NEUROVASCULAR COUPLING BY CORTICAL SOMATOSTATIN INTERNEURONS

Neurovascular coupling, which links neuronal activity to cerebral blood flow, is altered early in several neurological disorders and underlies functional brain imaging. This complex process involves multiple cellular players, with inhibitory interneurons in particular receiving increasing attention. Yet the mechanisms underlying how this process controls cerebral blood flow remain elusive. This study elucidates the mechanisms by which somatostatin interneurons bidirectionally control neurovascular coupling. Using patch-clamp recordings in cortical slices from mouse expressing channelrhodopsin-2 in somatostatin interneurons, we observed that these neurons are supralinearly activated by low-frequency (< 5 Hz) photostimulation and are efficiently activated at frequencies up to 20 Hz. Ex vivo and in vivo vascular imaging showed that low-frequency (2 Hz) photostimulation triggers vasodilation whereas high-frequency (20 Hz) photostimulation induces vasoconstriction, both dependent on action potential firing. Histochemical analysis revealed that subpopulations of cortical somatostatin interneurons express NOS-1, the neuronal synthesizing enzyme of the vasodilator nitric oxide, and/or the vasoconstrictor neuropeptide Y at much greater extents. Consistently, pharmacological investigations have shown that vasodilation induced by low-frequency optogenetic stimulation involves nitric oxide release and activation of its vascular receptor soluble guanylate cyclase. In contrast, the vasoconstriction induced at high-frequency photostimulation involves neuropeptide Y release and activation of the Y1 vascular receptor. These findings provide valuable insights into neurovascular coupling and help to understand the cellular mechanism underlying the functional brain imaging signals used to map brain function in both health and disease.