Investigating mechanisms of hemodynamic control in the brain

Neurovascular coupling is the relationship between neural activity and blood flow that allows the brain to exhibit increases in blood flow to areas of elevated neural activity during sensory stimulation. It is these localized changes in blood flow, collectively known as the hemodynamic response, that are detected by modern neuroimaging techniques such as functional magnetic resonance imaging (fMRI). Intact neurovascular coupling is imperative to neural health as de-coupling of neural activity from blood flow modulations has been implicated in many neurodegenerative diseases such as Alzheimer's disease, dementia, traumatic brain injury, and ischemic stroke. Despite the importance of neurovascular coupling for both fMRI interpretation and neurological disease, the mechanisms underlying the control of blood flow in the brain remain poorly understood. While previous studies have proposed a range of different cellular mechanisms capable of mediating vascular changes in the brain, it remains difficult to reconcile these mechanisms with a unified theory that is also consistent with the complex spatiotemporal features of the hemodynamic response. The goal of this dissertation is to study the vascular components of the hemodynamic response and the cellular mechanisms that orchestrate them. Using novel high-speed multi-spectral optical imaging of the exposed rodent somatosensory cortex, a detailed characterization of the cortical hemodynamic response is conducted. These observations guide cellular level two-photon microscopy of neural and glial cell activity. The precise spatiotemporal characteristics of the neurovascular response elucidated in these in vivo studies are then used to construct and constrain a conceptual framework for the signaling and actuation pathways that orchestrate the hemodynamic response. To test this framework, targeted light-dye treatment and optogenetic stimulation are used to selectively activate or deactivate targeted signaling pathways. The findings of this research strongly suggest that at least two different mechanisms control the sensory-evoked blood flow response, the first of which critically depends on the vascular endothelium.