Developing Methodologies to Explore Neurovascular Coupling on a Micron Scale

During brain activity, local oxygen and glucose is consumed and cerebral blood flow (CBF) increases in a process known as functional hyperemia or neurovascular coupling. Neurotransmission releases molecules that respond through post-synaptic neurons, astrocytes, and cerebral blood vessels to stringently regulate CBF supply according to local demand. If coupling between metabolic supply and demand is not met, energy deficits can lead to toxin accumulation, pathology, and even cell death. Functional magnetic resonance imaging (fMRI) is a popular method used to monitor neurovascular regulation and study brain functionality. However, recent studies show that the neurovascular heterogeneity can produce decoupled hyperemia at high spatial resolutions in healthy subjects, making interpreting fMRI data less certain and necessitating a better understanding of the underlying mechanisms behind neurovascular coupling. Here, we developed additional tools with which to probe neurovascular coupling at highly localized environments. We adapted an existing CBF measuring technique to a microfabricated format and proved its functionality through mathematical modeling and in vitro verification. Next, we adapted a multimodal sensor to detect oxygen changes and neuronal activity resultant of local, chemically selective glutamate stimulation using iontophoresis. Comparing glutamate iontophoresis to electrically stimulated glutamate release revealed key differences between the local cerebrovascular responses to stimuli of different specificities and intensities. We extended the multimodal sensor to modulate local glutamatergic receptor pharmacology and discovered that glutamate exerts influence on neurovascular coupling differentially between the somatosensory cortex and the nucleus accumbens. These tools provide alternative ways to measure multiple physiological metrics related to neurovascular coupling simultaneously. Our multimodal sensors offer chemical and spatial selectivity, and can assess neurovascular changes throughout the brain with minimal invasiveness. Together, our work demonstrates the importance of considering brain heterogeneity at the local level in the interpretation of more broad brain functionality studies.Doctor of Philosoph