Sunday, May 18, 2025
5/18/2025
Uncovering the physiological role of functional hyperemia - Neuronal activation leads to increases in blood flow to the region. Since its discovery in the 19th century, this phenomenon – termed functional hyperemia – has been thought to provide increased energy nutrients to sustain the increased neural activity. Impaired functional hyperemia is seen in many neurodegenerative diseases including Alzheimer's disease (AD). However, these diseases also manifest reduced baseline flow levels, making it difficult to determine the importance of functional hyperemia per se in sustaining healthy neuronal function. Functional hyperemia also forms the basis of many imaging techniques (such as fMRI), that take advantage of the spatially localized blood flow increase to infer the location of neural activity from vascular/metabolic measures. Despite the widespread importance of understanding functional hyperemia for neuroscience, the impacts of eliminating only the activity-induced increase in blood flow – without altering baseline flow levels or the activity of neurons and other cortical cells – are still unknown. This proposal will determine how neuronal activity and neuro-metabolism are affected in health and in Alzheimer's disease when functional hyperemia is blocked. We recently developed a model system to block functional hyperemia using optogenetics. To our surprise, we found that sensory-evoked neuronal responses were not diminished when functional hyperemia was blocked. In Aim 1 we will build on this preliminary data by studying what aspects of neural responses to sensory stimuli are altered by the loss of functional hyperemia. Two- photon calcium imaging will be used in mouse primary visual cortex to quantify how the response amplitude and selectivity to stimulus attributes (orientation selectivity) of excitatory and inhibitory neurons are affected. Using electrophysiology, we will determine if temporally precise aspects of neuronal activity, such as spike timing and network synchrony (i.e. gamma oscillations) are altered. Our working hypothesis is that blocking functional hyperemia impairs the cellular machinery involved in generating action potentials (such as restoring ion gradients). However, these consequences may not initially appear as reduced response levels, but rather as alterations in spike timing, excitatory/inhibitory balance, network synchrony, and information encoding. We will also determine if healthy young brains have the capacity to buffer the loss of functional hyperemia in ways that a diseased brain cannot by blocking functional hyperemia in a mouse model of AD. This will also shed light on the relative importance of reduced functional hyperemia versus baseline flow levels in AD pathology. In Aim 2 we will study how neuronal metabolism is affected by blocking functional hyperemia. We will record the concentrations of oxygen, glucose, lactate and ATP in the tissue to determine how blocking functional hyperemia affects the levels of these metabolites and if it leads to altered metabolic processing in neurons. We will also quantify how the vasculature reacts to temporary reductions in blood flow. This proposal will define the role functional hyperemia plays in maintaining the moment-to-moment metabolic needs of neurons.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).