Neurovascular coupling (NVC) links increases in neuronal activity with a rapid and spatially restricted increase
in local blood flow. Knowledge on the cellular mechanisms driving NVC has been focused on transient
exteroceptive sensory stimulation and limited to superficial dorsal brain areas (cortex). Thus, less is understood
on NVC dynamics of deeper brain regions, which can be activated by slow, sustained, and widespread stimuli
(e.g., physiological disturbances of bodily homeostasis). Derangement in homeostatic processes is a key driver
of pathological mechanisms in prevalent diseases such as neurohumoral activation in heart failure (HF). To
address this critical gap in our knowledge, we developed a novel experimental approach that enables
interoceptive-induced NVC during a challenge to bodily homeostasis. Our preliminary data show that contrary to
the canonical NVC response, a systemic and physiological homeostatic challenge (acute salt-loading)
progressively increased vasopressin (VP) neuronal firing, evoked activity-dependent vasoconstriction and
decreased local blood flow in the hypothalamic supraoptic nucleus (SON). The salt-induced inverse NVC (iNVC)
response was slow, sustained and widespread, and mediated by the dendritic release of VP within the SON.
iNVC resulted in local tissue hypoxia, which evoked further excitation of VP neurons. Based on these
observations, we hypothesize that iNVC is a physiological process that contributes to positive feedback
modulation of the VP neuronal population so that the physiological disturbance can be efficiently corrected. Still,
the precise signaling mechanisms and cellular targets mediating this novel physiological modality of NVC, and
more importantly, whether an aberrant iNVC response contributes to exacerbated VP neuronal activity
characteristic of prevalent cardiometabolic diseases, such as HF, remains unknown. Using a multidisciplinary
approach, in Aim 1 we will elucidate the precise signaling mechanisms and cellular targets mediating activity-
dependent iNVC in the SON (neuron-to-vessel signaling). In Aim 2, we will determine the mechanisms and
targets by which the iNVC evokes the positive feedback modulation of VP neuronal firing activity (vasculo-to-
neuron signaling). Finally, in Aim3, we will elucidate mechanisms contributing to exacerbated iNVC-mediated
positive feedback regulation of VP neurons in a disease state (HF). Both in vivo and ex vivo novel approaches
(2-photon imaging, patch-clamp electrophysiology, and ex vivo cannulation of SON arterioles) will be used in
novel transgenic rat models that enable visualization (eGFP) and manipulation (opto- and chemogenetically) of
VP neurons in the SON. The activation of acid-sensing ion channels (ASIC) and modulation of astrocyte
glutamate transporters will be investigated as key molecular targets. We expect results from this work to
contribute to a better understanding of fundamental mechanisms underlying NVC responses in different brain
regions and under different activity-dependent modalities. Moreover, we anticipate our studies to unveil novel
pathological mechanisms and therapeutic targets for the treatment of highly prevalent cardiometabolic diseases.
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