Belzic, E. | Search bioRxiv

bioRxiv2024

Bidirectional control of neurovascular coupling by cortical somatostatin interneurons

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is altered early in neurological disorders and underlies functional brain imaging. This process involves numerous cellular players. Among them inhibitory interneurons receive increasing attention, but how they control blood flow remains elusive. This study elucidates the mechanisms by which somatostatin interneurons bidirectionally control neurovascular coupling. Patch clamp recordings in, ex vivo, cortical slices from mice expressing channelrhodopsin-2 in somatostatin interneurons, revealed that these neurons are supralinearly activated at low-frequencies (< 5 Hz) and efficiently photostimulated at frequencies up to 20 Hz. Ex vivo vascular imaging showed that low-frequency (2 Hz) photostimulation triggered vasodilation whereas high-frequency (20 Hz) photostimulation induced vasoconstriction. Histochemistry revealed that subpopulations of cortical somatostatin interneurons expressed the neuronal nitric oxide synthase, and/or neuropeptide Y to a greater extent. Consistently, pharmacological investigations showed that vasodilation induced by low-frequency photostimulation involves nitric oxide release and activation of 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.

neuroscience↗

bioRxiv2024

Elevated pyramidal cell firing orchestrates arteriolar vasoconstriction through COX-2-derived prostaglandin E2 signaling

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is essential for brain function and underpins functional brain imaging. Whereas mechanisms involved in vasodilation are well-documented, those controlling vasoconstriction remain overlooked. This study unravels the mechanisms by which pyramidal cells elicit arteriole vasoconstriction. Using patch-clamp recording, vascular and Ca2+ imaging in mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces vasoconstriction, correlating with firing frequency and somatic Ca2+ increase. Ex vivo and in vivo pharmacological investigations indicate that this vasoconstriction predominantly recruits prostaglandin E2 through the cyclooxygenase-2 pathway, and activation of EP1 and EP3 receptors. We also present evidence that specific interneurons releasing neuropeptide Y, and astrocytes, through 20-hydroxyeicosatetraenoic acid, contribute to this process. By revealing the mechanisms by which pyramidal cells lead to vasoconstriction, our findings shed light on the complex regulation of neurovascular coupling. Significance statementCerebral blood flow is tightly controlled by neuronal activity, a process termed neurovascular coupling which serves as the physiological basis for functional brain imaging widely used to map neuronal activity in health and diseases. While the prevailing view links increased neuronal activity with enhanced blood perfusion, our data suggest that elevated neuronal activity can also reduce cerebral blood flow. By optically controlling the activity of pyramidal cells, we demonstrate that these excitatory neurons induce vasoconstriction when their action potential firing is increased by releasing glutamate and lipid messengers. These findings update the interpretation of functional brain imaging signals and help to better understand the etiopathogenesis of epilepsy and Alzheimers disease, in which hyperactivity, hypoperfusion and cognitive deficits overlap.

neuroscience↗