Elsevier

Free Radical Biology and Medicine

Volume 73, August 2014, Pages 421-429
Free Radical Biology and Medicine

Original Contribution
Neurovascular coupling in hippocampus is mediated via diffusion by neuronal-derived nitric oxide

https://doi.org/10.1016/j.freeradbiomed.2014.05.021Get rights and content

Highlights

  • Nitric oxide is a mediator of neurovascular coupling in hippocampus.

  • Nitric oxide induces a time-, space-, and amplitude-coupled increase in local CBF.

  • Both radical dotNO and CBF dynamics are dependent on the activation of NMDA receptors and nNOS.

  • The CBF increase mediated by neuronal-derived radical dotNO depends on the activation of sGC.

Abstract

The coupling between neuronal activity and cerebral blood flow (CBF) is essential for normal brain function. The mechanisms behind this neurovascular coupling process remain elusive, mainly because of difficulties in probing dynamically the functional and coordinated interaction between neurons and the vasculature in vivo. Direct and simultaneous measurements of nitric oxide (radical dotNO) dynamics and CBF changes in hippocampus in vivo support the notion that during glutamatergic activation nNOS-derived radical dotNO induces a time-, space-, and amplitude-coupled increase in the local CBF, later followed by a transient increase in local O2 tension. These events are dependent on the activation of the NMDA-glutamate receptor and nNOS, without a significant contribution of endothelial-derived radical dotNO or astrocyte–neuron signaling pathways. Upon diffusion of radical dotNO from active neurons, the vascular response encompasses the activation of soluble guanylate cyclase. Hence, in the hippocampus, neurovascular coupling is mediated by nNOS-derived radical dotNO via a diffusional connection between active glutamatergic neurons and blood vessels.

Section snippets

Array for radical dotNO and CBF measurements

The radical dotNO sensors were fabricated as previously described [24]. Briefly, a single carbon fiber (30 µm Ø; Textron, Lowell, MA, USA) was encased in a glass capillary and pulled in a vertical puller. The protruding carbon fiber was cut to a tip length of 200±50 µm. The electrical contact between the carbon fiber and a copper wire was achieved by using conductive silver paint (RS, Northants, UK). To improve their analytical properties for in vivo measurements of radical dotNO, the sensors were coated with Nafion

Nitric oxide and cerebral blood flow changes: coupling in space, time, and amplitude

We have previously reported that a controlled and localized glutamate stimulus in the rat hippocampus promotes an instantaneous and transient elevation of radical dotNO concentration levels through the activation of ionotropic glutamate receptors [23]. By upgrading such experimental strategy, simultaneously measuring local CBF, we observed that a transient radical dotNO increase induced by glutamate ejection (0.5 nmol, 25 nl, 1 s), was followed, seconds later, by a transient change in CBF (Fig. 1). radical dotNO production was

Discussion

The mechanisms that regulate the synergy between cerebral microcirculation and local neuronal activity have been debated over a century without clear conclusions, in part because of the severe experimental limitations to measure the process in real time in the natural working environment. The identification of radical dotNO as a diffusible vasodilator produced at active neurons, via ionotropic glutamate receptor-dependent pathways, led to the hypothesis that it could be the mediator coupling the brain

Acknowledgements

This work was supported by FCT grant (Portugal) PTDC/SAU-NEU/108992/2008.

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