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.

Alterations in arterial CO2 rather than pH affect the kinetics of neurovascular coupling in humans

“…The NVC response was not affected by experimentally elevated arterial pH via intravenous NaHCO 3 at each matched stage across a wide range of (Table 3 and Figs 3 and 4). These novel data support recent pre‐clinical work by Hosford and colleagues (2021, preprint) that illustrate that CO 2 signalling (via astrocytic CO 2 /HCO 3 – transport) mediates NVC independently of experimentally altered resting CBF and arterial/extracellular pH. These well‐controlled experiments effectively abolished the NVC response with the provision of 10% inspired CO 2 after pharmacologically accounting for ‐induced elevations in CBF and reductions in arterial/extracellular pH (Hosford et al .…”

“…These well‐controlled experiments effectively abolished the NVC response with the provision of 10% inspired CO 2 after pharmacologically accounting for ‐induced elevations in CBF and reductions in arterial/extracellular pH (Hosford et al . 2021, preprint). Additionally, Hosford and colleagues (2021, preprint) utilized astrocyte‐specific genetic deletion of electrogenic Na + /HCO 3 – cotransporter 1 to affect extracellular CO 2 /pH balance and abolish NVC; collectively, these data substantiate that the NVC response is regulated by CO 2 signalling rather than an exhausted vasodilatory reserve and/or directly mediated by pH.…”

“…2021, preprint). Additionally, Hosford and colleagues (2021, preprint) utilized astrocyte‐specific genetic deletion of electrogenic Na + /HCO 3 – cotransporter 1 to affect extracellular CO 2 /pH balance and abolish NVC; collectively, these data substantiate that the NVC response is regulated by CO 2 signalling rather than an exhausted vasodilatory reserve and/or directly mediated by pH. Within the NVC response, the local extravascular pH initially becomes alkaline due to ‘H + wash‐out’ facilitated by the elevated CBF as well as intra‐/extracellular Ca 2+ /H + ‐ATPase exchange (Astrup et al .…”

“…Taken together, these findings support recent pre‐clinical work that CO 2 signalling mediates NVC independently of resting CBF and arterial/extracellular pH (Hosford et al . 2021, preprint). These results provide convincing experimental evidence in humans that alterations in , and related changes in cerebrovascular tone, affect the temporal responsiveness of NVC (Fig.…”

“…Additionally, recent pre‐clinical work substantiates that CO 2 signalling – including astrocytic CO 2 /HCO 3 – transport – mediates NVC independently of resting CBF and arterial/extracellular pH (Hosford et al . 2021, preprint). As changes in pH influence Ca 2+ sensitivity (Boedtkjer et al .…”