Functional mapping of spontaneous brain activity with resting-state functional connectivity (FC) analysis of fMRI data has recently become a dominant approach to mapping human brain function and continues to gain momentum. However fMRI is based on cerebral hemodynamics that is relatively indirectly coupled to neuronal activity and much slower (~0.3 Hz). Further the physiological underpinnings of FC are relatively un-resolved, such that the mechanisms and implications altered FC are often unclear. For example in ischemic stroke, it is well known that the penumbra surrounding the ischemic core has altered neurovascular coupling (NVC), complicating the interpretation of the FC deficits. As FC measures are extended further into studies of brain development, aging and disease, the importance of understanding the fundamental basis for FC will grow. We recently developed hemodynamic mapping of functional connectivity in mice using optical intrinsic signal imaging (fcOIS), and found fcOIS sensitive to several neurological diseases, including mouse models of stroke and Alzheimer's disease. However, with the advent of genetic engineering techniques for mice, there are new opportunities for extending optical wide-field imaging to calcium activity, which is >10x faster and more directly coupled to neural activity than hemoglobin. By combining calcium and hemodynamic imaging, there is the potential to quantify the relationship between cell-specific calcium dynamics and hemodynamics throughout brain regions. Further concurrent calcium and hemoglobin imaging could help resolve questions about the impact of altered NVC in diseases such as stroke, and in early brain development. However, as yet, no imaging system has been developed to examine these rich relationships throughout the mouse cortex. In this project, we will develop optical imaging hardware and software for characterizing calcium dynamics in mice engineered for genetically encoded calcium indicators (GECI's). For exemplar applications where the functional networks are changing quickly, we will quantify FC during stroke recovery and brain development, tracking the progression of both functional connectivity and neurovascular coupling (NVC).
Aim 1 will develop fluorescence molecular tomography (FMT) and diffuse optical tomography (DOT) instrumentation for concurrent mapping of calcium and hemoglobin in mice.
Aim 2 will optimize system performance for high speed FMT/DOT of mouse brain function.
Aim 3 will establish FMT/DOT for mapping the functional networks of cell-specific calcium signals in mice with GECIs. Concurrent imaging with hemoglobin will enable mapping of neurovascular coupling.
In aim 4, with establish feasibility of FMT/DOT in both stroke recovery and brain developmental. In both applications we will quantify calcium- FC and the influence of altered NVC on hemoglobin-FC.

Public Health Relevance

Mapping functional brain networks in humans using resting-state functional connectivity (FC) using blood dynamics is becoming an increasingly important assay of brain integrity during neurological disease, however the physiological underpinnings of FC have been relatively un- explored. Cell-specific, calcium activity, which is faster and more directly coupled to neural activity than hemodynamics could enhance our understanding of the fundamental physiology of hemoglobin-FC. This grant will develop neuroimaging technology for mice with genetically encoded calcium indicators (GECI's) that will enable us to quantify cell-specific, calcium activity and improve our understanding of the nature of changing or altered FC in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099429-04
Application #
9930669
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Babcock, Debra J
Project Start
2017-07-01
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Washington University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Bumstead, Jonathan R; Park, Jasmine J; Rosen, Isaac A et al. (2018) Designing a large field-of-view two-photon microscope using optical invariant analysis. Neurophotonics 5:025001
Mitra, Anish; Kraft, Andrew; Wright, Patrick et al. (2018) Spontaneous Infra-slow Brain Activity Has Unique Spatiotemporal Dynamics and Laminar Structure. Neuron 98:297-305.e6
Bauer, Adam Q; Kraft, Andrew W; Baxter, Grant A et al. (2018) Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse. Cereb Cortex 28:370-386
Wright, Patrick W; Brier, Lindsey M; Bauer, Adam Q et al. (2017) Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice. PLoS One 12:e0185759
Reisman, Matthew D; Markow, Zachary E; Bauer, Adam Q et al. (2017) Structured illumination diffuse optical tomography for noninvasive functional neuroimaging in mice. Neurophotonics 4:021102
Kraft, Andrew W; Mitra, Anish; Bauer, Adam Q et al. (2017) Visual experience sculpts whole-cortex spontaneous infraslow activity patterns through an Arc-dependent mechanism. Proc Natl Acad Sci U S A 114:E9952-E9961