Nitric oxide is not responsible for the initial sensory-induced neurovascular coupling response in mouse cortex

Abstract

Neurovascular coupling ensures that changes in neural activity are accompanied by localised changes in cerebral blood flow. While much is known about the involvement of excitatory neurons in neurovascular coupling, the role of inhibitory interneurons is unresolved. While nNOS-expressing interneurons have been shown to be capable of eliciting vasodilation, the role of nitric oxide in functional hyperemia remains a matter of debate. Therefore in the present study we applied a combination of optogenetic and pharmacological approaches, 2-dimensional optical imaging spectroscopy, and electrophysiology to investigate the role of nitric oxide in neurovascular coupling responses evoked by nNOS-expressing interneurons and whisker stimulation in mouse sensory cortex. The haemodynamic response evoked by nNOS-expressing interneurons was significantly altered in the presence of the NOS inhibitor LNAME, revealing a large initial 20-HETE-dependent vasoconstriction. In contrast, the haemodynamic response induced by sensory stimulation was largely unchanged by LNAME. Our results suggest that while nitric oxide plays a key role in neurovascular responses evoked by nNOS-expressing interneurons it does not mediate the initial sensory-induced neurovascular coupling response in mouse cortex. Thus, our results call into question the involvement of nNOS-expressing interneurons and nitric oxide in sensory-evoked functional hyperemia.

The Reversal Characteristics of GABAergic Neurons: A Neurovascular Model

“…4. Comparison of experimental data [18] and numerical model for whisker stimulation with LNAME injected shows the model results for the optogenetic condition when LNAME is introduced.…”

“…Experimental data are taken from experiments performed by Lee et al [18], in which full experimental details can be found. In brief, stimulation-evoked cortical haemodynamic responses were measured using 2-Dimensional Optical Imaging Spectroscopy (2D-OIS: [19]), which allows the measurement of relative changes in oxyhaemoglobin (HbO), deoxyhaemoglobin (HbR) and total haemoglobin (HbT).…”

“…These channels have a reversal potential of −75 mV and a channel conductance dependent on GABA; when GABA = 0, conductance = 0 and when GABA is at some maximal value, the conductance is also some maximal value G GABA . At present this maximum is taken as G GABA = 0.3 × G Cl,i where G Cl,i is the conductance of the SMC Clleak channel (value chosen to fit with Lee et al [18] experimental data). The conductance of the VOCC in the SMC is multiplied by an NPY dependent function such that when NPY= 0, the VOCC conductance g VOCC is equal to the regular conductance G Ca,i of the VOCC, and when NPY is at some maximal value g VOCC is equal to 1.05 × G Ca,i (value chosen to fit with the Lee et al [18] experimental data).…”

“…whilst the blue profile is the numerical simulation result . Figure 2 shows the comparison of experimental data [18] and numerical model for the case of 2 sec whisker stimulation before LNAME injection. Figure 3 α GABA non-dimensional production rate of GABA the optogenetic condition when no drug is introduced.…”

“…The parameter values for the full model (excluding the GABA/NPY components) were obtained through a two part sensitivity analysis and optimization routine. First through Monte Carlo sampling we were able to identify a subset of the parameters for which altering their values had significant impact upon the model's accuracy to the experimental data ( [18]). Then working with this much smaller set of parameters we minimized the discrepancy between the model's behaviour and the experimental data.…”