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

ABSTRACT Neurovascular coupling (NVC), linking neuronal activity to cerebral blood flow (CBF), 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 Emx1-Cre;Ai32 mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces arteriole vasoconstriction, correlating with firing frequency and somatic Ca2+increase.Ex vivoandin vivopharmacological investigations indicate that this neurogenic vasoconstriction extends beyond glutamatergic transmission and predominantly recruits prostaglandin E2 (PGE2) through the cyclooxygenase-2 (COX-2) pathway, and activation of EP1 and EP3 receptors. Single-cell RT-PCR further identifies layer II/III pyramidal cells as a key source of COX-2-derived PGE2. Additionally, we present evidence that specific neuropeptide Y (NPY) interneurons acting on Y1 receptor, and astrocytes, through 20-hydroxyeicosatetraenoic acid (20-HETE) and COX-1-derived PGE2, contribute to this process. By revealing the mechanisms by which the activity of pyramidal cells leads to vasoconstriction, our findings shed light on the complex regulation of CBF.Significance statement Cerebral 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 Alzheimer’s disease, in which hyperactivity, hypoperfusion and cognitive deficits overlap..

Medienart:	Preprint

Erscheinungsjahr:	2024
Erschienen:	2024

Enthalten in:	bioRxiv.org - (2024) vom: 11. Apr. Zur Gesamtaufnahme - year:2024

Sprache:	Englisch

Beteiligte Personen:	Gac, B Le [VerfasserIn] Tournissac, M [VerfasserIn] Belzic, E [VerfasserIn] Picaud, S [VerfasserIn] Dusart, I [VerfasserIn] Soula, H [VerfasserIn] Li, D [VerfasserIn] Charpak, S [VerfasserIn] Cauli, B [VerfasserIn]

Links:	Volltext [kostenfrei]

Themen:	570 Biology

doi:	10.1101/2024.03.27.586974

funding:
Förderinstitution / Projekttitel:

PPN (Katalog-ID):	XBI043103197