# Project 1

> **NIH NIH U19** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2022 · $550,295

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 1
 We propose to leverage our state-of-the-art expertise in vivo optical imaging and data analysis, combined
with behavioral training, electrophysiology, and modeling, to investigate fundamental aspects of the pial
neurovascular circuit in mice. This circuit is composed of a fully connected albeit irregular lattice of pial
arterioles that undergo rhythmic oscillations - in the ~ 0.1 Hz vasomotor band - in isolation. The pial circuit
integrates neuronal activity from neighboring vessels, underlying neurons, and subcortical regions to produce
dynamic patterns of coherent oscillations in arteriolar diameter across the cortical mantel. These patterns
contain regions at slightly different frequencies, i.e., they parcellate, in a manner that partially reflects the
underlying neuronal input. We seek to understand and model this parcellation, which is readily measured with
optical and functional MR imaging, and quantify how it defines brain state.
 Aim 1 seeks to formulate an understanding of fundamental physiology of the pial neurovascular circuit. This
includes testing if brain arterioles truly act as non-linear interacting oscillators, so that they entrain and phase
lock rather than passively filter. In Aim 2 we explore the competitive conditions that break locking between
oscillators so that parcellation can occur. These experiments gain from our ability to use sensory stimuli from
different modalities - touch, vision and audition - each of which targets a different brain area. They also gain
from our ability to drive subcortical inputs, particularly those involved in homeostatic brain function, and use
direct optogenetic stimulation where needed. Lastly, these experiments gain from interaction with the
neuromodulatory investigations of Project 2, as subcortical neuromodulation provides both regional and
cortex-wide control of neuronal excitability.
 The experimental plan is motivated by the theory of phase-coupled oscillators that dates from Yoshiki
Kuramoto's 1975 Lecture Notes. In this regard, progress on Aims 1 and 2 are strongly interwoven with the
theory effort of Project 4.
 Aim 3 will connect the dynamics of the pial neurovascular circuit with the dynamics of the penetrating
arterioles; these vessels source energy substrates to the parenchyma. These experiments, also in rodents,
involve deep imaging of the cerebral mantel with CBV fMRI and adaptive optics two photon imaging. Together
with direct measurements of oxygen transport in Project 2, these data provide input for calculations of oxygen
tension throughout the cortical mantle. This, in turn, provides a means to couple BOLD fMRI and/or CBV fMRI
to pial neurovascular dynamics.
 All told, the experimentation and analysis of Project 1 will provide a way forward to infer the state of the
human mind from MR imaging (Project 3).

## Key facts

- **NIH application ID:** 10470265
- **Project number:** 5U19NS123717-02
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** David Kleinfeld
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $550,295
- **Award type:** 5
- **Project period:** 2021-08-16 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470265

## Citation

> US National Institutes of Health, RePORTER application 10470265, Project 1 (5U19NS123717-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10470265. Licensed CC0.

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