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CO₂ signaling mediates neurovascular coupling in the cerebral cortex.

ABSTRACT: Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in the somatosensory cortex are prevented by saturation of the CO₂-sensitive vasodilatory brain mechanism with surplus of exogenous CO₂ or disruption of brain CO₂/HCO₃^- transport by genetic knockdown of electrogenic sodium-bicarbonate cotransporter 1 (NBCe1) expression in astrocytes. A systematic review of the literature data shows that CO₂ and increased neuronal activity recruit the same vasodilatory signaling pathways. These results and analysis suggest that CO₂ mediates signaling between neurons and the cerebral vasculature to regulate brain blood flow in accord with changes in the neuronal activity.

SUBMITTER: Hosford PS

PROVIDER: S-EPMC9019094 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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CO<sub>2</sub> signaling mediates neurovascular coupling in the cerebral cortex.

Hosford Patrick S PS Wells Jack A JA Nizari Shereen S Christie Isabel N IN Theparambil Shefeeq M SM Castro Pablo A PA Hadjihambi Anna A Barros L Felipe LF Ruminot Iván I Lythgoe Mark F MF Gourine Alexander V AV

Nature communications 20220419 1

Neurovascular coupling is a fundamental brain mechanism that regulates local cerebral blood flow (CBF) in response to changes in neuronal activity. Functional imaging techniques are commonly used to record these changes in CBF as a proxy of neuronal activity to study the human brain. However, the mechanisms of neurovascular coupling remain incompletely understood. Here we show in experimental animal models (laboratory rats and mice) that the neuronal activity-dependent increases in local CBF in ...[more]

PMID: 35440557

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Project description:Vasodilatory prostaglandins play a key role in neurovascular coupling (NVC), the tight link between neuronal activity and local cerebral blood flow, but their precise identity, cellular origin and the receptors involved remain unclear. Here we show in rats that NMDA-induced vasodilation and hemodynamic responses evoked by whisker stimulation involve cyclooxygenase-2 (COX-2) activity and activation of the prostaglandin E2 (PgE2) receptors EP2 and EP4. Using liquid chromatography-electrospray ionization-tandem mass spectrometry, we demonstrate that PgE2 is released by NMDA in cortical slices. The characterization of PgE2 producing cells by immunohistochemistry and single-cell reverse transcriptase-PCR revealed that pyramidal cells and not astrocytes are the main cell type equipped for PgE2 synthesis, one third expressing COX-2 systematically associated with a PgE2 synthase. Consistent with their central role in NVC, in vivo optogenetic stimulation of pyramidal cells evoked COX-2-dependent hyperemic responses in mice. These observations identify PgE2 as the main prostaglandin mediating sensory-evoked NVC, pyramidal cells as their principal source and vasodilatory EP2 and EP4 receptors as their targets.Significance statementBrain function critically depends on a permanent spatiotemporal match between neuronal activity and blood supply, known as NVC. In the cerebral cortex, prostaglandins are major contributors to NVC. However, their biochemical identity remains elusive and their cellular origins are still under debate. Although astrocytes can induce vasodilations through the release of prostaglandins, the recruitment of this pathway during sensory stimulation is questioned. Using multidisciplinary approaches from single-cell reverse transcriptase-PCR, mass spectrometry, to ex vivo and in vivo pharmacology and optogenetics, we provide compelling evidence identifying PgE2 as the main prostaglandin in NVC, pyramidal neurons as their main cellular source and the vasodilatory EP2 and EP4 receptors as their main targets. These original findings will certainly change the current view of NVC.

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CO₂ signaling mediates neurovascular coupling in the cerebral cortex.

Publications

CO<sub>2</sub> signaling mediates neurovascular coupling in the cerebral cortex.

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CO2 signaling mediates neurovascular coupling in the cerebral cortex.

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CO&lt;sub&gt;2&lt;/sub&gt; signaling mediates neurovascular coupling in the cerebral cortex.

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OmicsDI is part of the ELIXIR infrastructure

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CO₂ signaling mediates neurovascular coupling in the cerebral cortex.

CO<sub>2</sub> signaling mediates neurovascular coupling in the cerebral cortex.