A neurovascular coupling model based on nitric oxide and carbon dioxide and its validation with two-photon microscopy imaging

Abstract

Understanding neurovascular coupling is of paramount importance since while a normal coupling is vital for a healthy functioning brain, the impairment in coupling is the underlying factor of many neurodegenerative diseases. With this motivation, we aimed to test the still-debatable hypotheses and important aspects of neurovascular coupling: whether the coupling is controlled metabolically or neurogenically, how the coupling is propagated, what kinetics the cerebral metabolic rate of oxygen (CMRO2) follows during neuronal activity and the transient characteristics of the response during stimulus and after stimulus periods. We have modi ed recent models of neurovascular coupling adding the e ects of both nitric oxide (NO) kinetics, a well-known neurogenic vasodilator, and CO2 kinetics as a metabolic vasodilator to test the neurogenic and metabolic hypotheses. Using 2-photon microscopy imaging, we measured the vessel diameter changes in vivo in somatosensory cortex of Sprague Dawley rats during forepaw stimulation to investigate response transients and to test retrograde dilation hypothesis. Our results show that the dominant factor in the hemodynamic response is NO, however CO2 is important in modulating the shape of the response: causing poststimulus undershoot due to the washout e ect of cerebral blood ow (CBF) resulting in hypocapnia. The statistical analysis of our experimental results and their comparison with the modeling results give more insight into the transient characteristics of the response. Our results support retrograde dilation hypothesis and suggests a CMRO2 onset and return kinetics in seconds rather than in minutes during functional activity.|Keywords: Neurovascular coupling, Neurogenic hypothesis, Metabolic hypothesis, Nitric oxide, Carbon dioxide, 2-photon microscopy.