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Principal Investigator: ALBERTO L VAZQUEZ
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $515,456
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
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.
Terms: <Air><Animals><Autopsy><BNOS><Basic Research><Basic Science><Blood Vessels><Blood flow><Body Tissues><Brain><Brain Nervous System><Brain imaging><Brain region><Cell Communication and Signaling><Cell Signaling><Cerebrovascular system><Clinical><Clinical Research><Clinical Study><Cognitive><Complex><Cyclic Somatostatin><Development><Disease><Disorder><Dysfunction><EDRF Synthase><Early Diagnosis><Encephalon><Endothelium-Derived Growth Factor Synthase><Experimental Designs><Fluorescence><Foundations><Functional MRI><Functional Magnetic Resonance Imaging><Functional disorder><GABA Receptor><Glutamate Receptor><Goals><Growth Hormone Inhibiting Factors><Growth Hormone-Inhibiting Hormone><Guanylyl Cyclase-Activating Factor Synthase><Head><Health><Human><Image><Intracellular Communication and Signaling><Location><Measures><Methods><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><NC-NOS><NNOS><NO Synthase><NOS 1 protein><NOS type I><NOS1 protein><Nerve Cells><Nerve Degeneration><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neural Constitutive Nitric Oxide Synthase><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuron Degeneration><Neurons><Nitric Oxide Synthase><Nitric Oxide Synthase Type I><Nitric-Oxide Synthetase><Optical Methods><PHM27><Parvalbumins><Pathway interactions><Physiology><Physiopathology><Population><Position><Positioning Attribute><Regulation><Reporter><Reporting><Rest><Role><SRIH><SRIH-14><Sensory><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Somatosensory Cortex><Somatostatin><Somatostatin-14><Somatotropin Release Inhibiting Factors><Somatotropin Release-Inhibiting Hormone><Techniques><Tissues><Transgenic Mice><Vascular blood supply><Vasoactive Intestinal Peptide><Vasoactive Intestinal Polypeptide><Vasointestinal Peptide><Vibrissae><Viral><Whiskers><Work><abnormal brain function><awake><biological signal transduction><blood supply><blood vessels in the brain><brain blood vessels><brain dysfunction><brain impairment><brain nitric oxide synthase><brain vasculature><brain visualization><cell cortex><cell type><cerebral blood vessel><cerebral vasculature><cerebrovascular vessels><cerebrovasculature><design><designing><developmental><dysfunctional brain><early detection><experiment><experimental research><experimental study><experiments><fMRI><frontal cortex><frontal lobe><gamma-Aminobutyric Acid Receptors><growth hormone release inhibiting factor><hemodynamics><human subject><imaging><imaging study><improved><inhibitory neuron><insight><mouse model><multi-modality><multimodality><murine model><nNOS enzyme><necropsy><neural><neural degeneration><neuro-vascular><neurodegeneration><neurodegenerative><neurological degeneration><neurological disease><neuronal><neuronal NOS><neuronal degeneration><neuronal form of nitric oxide synthase><neuronal nitric oxide synthase><neurovascular><nitric oxide synthase 1><optic imaging><optical imaging><optogenetics><pathophysiology><pathway><postmortem><response><social role><somesthetic sensory cortex><vascular><vascular supply>