Inverse Neurovascular Coupling Contributes to Vasopressin Neuronal Activation in Response to Systemic Homeostatic Challenge

Abstract

Neurovascular coupling (NVC), the process that links neuronal activity to cerebral blood flow changes, has been mainly studied in superficial brain areas, namely the neocortex. Still, whether the conventional, rapid and spatially restricted NVC response can be generalized to deeper, and functionally diverse brain regions remains unknown. The hypothalamic supraoptic nucleus (SON) is a deep brain region with unique cytoarchitectural properties including a high vascularization. Paradoxically, the dense vascular network is not required to maintain its metabolic demand. This mismatch in metabolic supply and demand suggests that the SON vasculature may serve additional functions beyond the delivery of energy substrates. To address this important gap in our knowledge, we set up the objective to implement a novel experimental approach to enable in vivo, real‐time two‐photon imaging from the ventral surface of the brain to monitor SON NVC responses to a systemic homeostatic challenge. Using this approach in anaesthetized male and female transgenic rats expressing GFP driven by the vasopressin (VP) promoter (VP‐GFP rats), we found that a systemic hypertonic saline (HTS) infusion evoked a gradual and linear increase in the firing rate of VP neurons (p < 0.0001; n = 4). Rather than resulting in a classical vasodilatory NVC, the increased VP neuronal activity was accompanied by a significant intraparenchymal arteriole (but not venule) vasoconstriction (one‐way RM ANOVA; p < 0.0001; n = 13 vessels from 5 rats). This “inverse” NVC was prevented when a VP V1a receptor antagonist was locally delivered within the SON (one‐way RM ANOVA; p < 0.0001; n = 4 vessels from 4 rats). The HTS infusion also significantly decreased RBC velocity in SON capillaries (one‐way RM ANOVA; p < 0.0001; n = 17 vessels from 6 rats) indicative of a decreased SON blood flow. The salt‐induced inverse NVC response resulted in a rapid and progressive decrease in SON pO2 (one‐way RM ANOVA; p < 0.002; n = 6 rats), along with an increased expression of the hypoxia inducible factor (HIF)‐1a mRNA (p < 0.001; one‐sample t test n = 6 rats). Finally, we show that a hypoxic SON microenvironment significantly increased the firing activity of VP neurons in ex vivo slices (p < 0.02; paired t test; n = 14 cells from 10 rats). Taken together, we show that the salt‐induced inverse NVC in the SON results in a hypoxia‐mediated positive feedback mechanism, which we propose contributes to sustain the activity of VP neurons in response to a systemic homeostatic challenge.