Regulation of Cerebral Blood flow by Intrinsic Neuromodulation in Wakefulness and Sleep

Boston University (Charles River Campus), Boston MA

Investigators

Abstract

PROJECT SUMMARY Noninvasive functional imaging techniques, such as functional Magnetic Resonance Imaging (fMRI), have a potential for diagnosing neurological diseases and evaluation of treatments. However, to fully realize this potential, we need better understanding of the process known as neurovascular coupling (NVC). My recent study in mice revealed that, during resting state, hemodynamic fluctuations depend on norepinephrine (NE), an intrinsic vasoactive neuromodulator. Using my experimental measurements, I derived a simple model that predicted hemodynamics across the cerebral cortex with high accuracy given a measure of NE and local circuit activity. The proposed study aims to extend these results to other brain states and neuromodulatory neurotransmitters. In Aim 1, I will use widefield imaging of the entire dorsal cortical surface to image neural calcium activity, release of a neuromodulator (ACh, NE, DA, or 5-HT), and fluctuations in oxy/deoxy/total hemoglobin. These optical measures, together with EMG and µECoG recordings, will be used to label brain state, which will be used to relate fluctuations in neuromodulator release to brain state-specific hemodynamics. Then, for each brain state, I will identify and formalize the dependence of hemodynamics on the relevant neuromodulatory neurotransmitters in terms of the Impulse Response Function (IRF) used in fMRI studies. My Aim 2 is a mechanistic counterpart of Aim 1. In Aim 2, I will evaluate the causal relationship between the release of a specific neuromodulator and hemodynamic fluctuations across brain states. To this end, I will use two-photon microscopy to measure dilation of single cortical arterioles simultaneously with neural calcium activity and neuromodulator release. I will use pharmacological tools and opto/chemogenetics to block the receptors or neuromodulatory release while simultaneously tracking brain state transitions. The results of this project will (a) deliver new mechanistic knowledge about the regulation of cerebral blood flow by neuromodulation, across brain states, and (b) inform the choice of IRF in fMRI studies. Beyond the current scope, these results would allow asking the question of whether release of specific neuromodulators can be predicted from noninvasive hemodynamic signals, something that I am interested to explore during my future postdoctoral training. For my long-term career, I intend to apply engineering principles to neuroscience questions and combine mechanistic animal studies with computational modeling, as a leader of a research group in an academic institution. The goal of my training plan is to (1) expand my scientific knowledge base in neurophotonics and computational neuroscience, (2) develop novel concepts about specific mechanisms that govern neurovascular coupling and generation of hemodynamic signals, (3) present my results at international forums and produce high-profile publications, and (4) expand a network of colleagues and collaborators.