Neuronal activity actively modulates local cerebral vasculature. This neuro-vascular interaction is the foundation of imaging studies of human brain function in health and disease. These studies are routinely performed while subjects perform tasks (evoked activity) or lie resting (task-free or resting-state activity), and they assume that imaging signals loyally reflect local neuronal activity. However, the neuro-vascular signaling mechanism is complex and instances of uncoupling have been reported, limiting the interpretability of these studies. Recent reports have shown that different types of neurons can regulate local blood supply stronger than others, especially inhibitory neurons. These findings underscore the need to understand the vaso-regulatory roles of different neuronal populations, especially considering that neurological disorders have been associated with dysfunction of specific inhibitory neuron sub-populations. The goal of this proposal is to determine the role of different sub-populations of inhibitory neurons on the regulation of local blood flow during evoked stimulation as well as during resting-state activity periods. Experiments will be performed using unique transgenic mouse models. In addition, we will determine whether these findings generalize over different cortical regions and explore the translatability of these findings to human subjects by comparing the distribution of inhibitory neurons that strongly regulate local blood flow in targeted regions of mouse and human brains. Our group has extensive multi-modal expertise in neuro-vascular (and neuro-metabolic) physiology, including the models and techniques proposed, and we are uniquely positioned to successfully complete the aims of this project. We will achieve these goals through three aims:
(Aim 1) Determine which inhibitory neuron sub-types strongly regulate local blood flow changes evoked by optogenetic stimulation in different cortical regions;
(Aim 2) Determine whether the same sub-population of inhibitory neurons regulate local blood flow changes during ongoing awake activity periods;
and (Aim 3) Determine whether the sub-populations of inhibitory neurons identified in Aims 1 and 2 are similarly distributed across the targeted regions of mouse and human brains. Since inhibitory neurons shape network activity, these studies will detail the impact of specific inhibitory neuronal sub-type function and dysfunction on local blood supply and hemodynamic-based imaging signals, expanding the interpretability and clinical utility of human brain imaging studies in health and disease.
The hemodynamic response induced by neural activity is the principal means of studying brain function and brain connectivity in humans and animals. Methods like functional magnetic resonance imaging (fMRI) and optical imaging of intrinsic signal (OIS) are essential in basic science, developmental, cognitive and clinical studies of normal and impaired brain function. This proposal will reveal the contributions of sub-populations of inhibitory neurons on vascular regulation and imaging signals like fMRI and OIS to improve our understanding of brain function and dysfunction in health and disease.
