Date of Award

2018

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

Andy Shih

Second Advisor

Narayan Bhat

Third Advisor

Prakash Kara

Fourth Advisor

David Kleinfeld

Fifth Advisor

Arthur Riegel

Sixth Advisor

Alejandro Spiotta

Abstract

The cerebrovasculature modulates its resistance to flow in order to match blood supply with the high metabolic demand of the brain. While it is accepted that vascular smooth muscle cells are capable of modulating blood flow resistance through arterioles, whether pericytes can similarly regulate blood flow through capillaries has been a topic of debate for over 100 years. First we used new transgenic mice to characterize the structural spectrum of pericytes in the brain, and found a wide range of pericyte shapes that could be grouped into two main pericyte types. We then mapped where these “ensheathing pericytes” and “capillary pericytes” live along the cerebrovascular tree, and stimulated one or two of them at a time in vivo using two photon optogenetics through a cranial window. We found that both types of pericytes can constrict their underlying blood vessel in a way that decreases local blood flow. Importantly, vascular smooth muscle cells exhibited much more dramatic constriction upon stimulation, indicating that pericytes modulate blood flow in a slower and subtler way than do vascular smooth muscle cells. To investigate if pericytes use this ability to modulate blood flow under physiological conditions, we ablated one or two capillary pericytes in the living brain. We were surprised to find that 3 days after ablation we observed a dilation of capillaries left uncovered by the pericyte ablation, which corresponded with a doubling in the number of red blood cells flowing through that capillary. Critically, we did not observe any hemodynamic changes in control animals that either did not express optogenetic proteins, or did not have any pericytes ablated. The results therefore suggest that pericytes play a role in shaping capillary blood flow through the brain. This will inform the longstanding debate, and could lead to new ways of correcting blood flow abnormalities that plague numerous neurological diseases like traumatic brain injury, epilepsy, and stroke.

Rights

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