Mechanisms underlying neurovascular coupling

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Neurovascular coupling (NVC) -the dynamic linkage between neuronal energy needs and local blood supply- is critical to the maintenance of brain homeostasis. In the brain, increased neuronal synaptic activity is accompanied by an increase in local cerebral blood flow (CBF) that serves to satisfy enhanced glucose and oxygen demand. Beside its crucial physiological role, a better understanding of the mechanisms underlying NVC is very important because this concept is at the basis of modern neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). Despite the fact that these techniques are, in fact, measuring cerebral oxygen, glucose or CBF levels and that the relationship between these variables and neuronal activity are non-linear, results are still falsely interpreted as a direct reflection of neuronal activity. It is thus imperative to better understand the mechanisms underlying NVC. Among the vasoactive factors that could participate in NVC, one powerful vasodilator and endogenously produced gas have been identified, nitric oxide (NO). NO may potentially act on all type of cells of the neurovascular unit (neurons, astrocytes and vascular cells). Astrocytes, which are uniquely positioned between synapses and vessels, have been recognized as integrators of the neuronal signals to relay information to the vessels and could be an interesting target and source of NO. We indeed demonstrated that astrocytes produce NO upon different neurological stimulations. The major focus of the present proposal is to understand how NO and astrocytic signaling pathways interact together to modulate NVC. We HYPOTHETIZE that NO modulates NVC mostly but not uniquely by regulating astrocytic-dependent pathways. To verify this hypothesis, we propose three specific AIMS: 1) To elucidate the effect of NO on Ca2+-dependent astrocytic pathways in the context of NVC ; 2) To elucidate how astrocytic nNOS and eNOS mediated NO production regulates NVC ; 3) To discriminate the importance of NO from interneurons, pyramidal neurons and astrocytes in NVC. These mechanisms will be studied using transgenic mice and pharmacological tools with two-photon microscopy and laser Doppler flowmetry. The proposed concept is very INNOVATIVE because it is assumed that NO is produced by neurons or endothelial cells to act as vasodilators whereas the potential presence of astrocytic NO had been ignored. It also suggests that each constitutive NOS in astrocytes is associated to a specific pathway and possibly to a specific function. The LONG-TERM GOALS are to define the mechanisms underlying NVC and to verify how these findings correlate with MRI signals. RELEVANCE: results obtained from the present proposal will greatly enhance our understanging of how neural activity is related to CBF and may help to understand, improve and develop brain imaging techniques.