Biomedical Sciences ETDs

Publication Date

Spring 4-13-2017

Abstract

Spreading depolarization (SD) is a propagating wave of neuronal activation occurring in the central nervous system. SD is accompanied by depression of synaptic activity and complex blood flow changes. Better understanding the mechanisms underlying these phenomena may be important to elucidate the pathophysiology of human disease, and to develop therapeutic interventions. SD contributes significantly to the morbidity and mortality of thromboembolic and ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. Experiments described in this dissertation were designed to investigate the regulation of neuronal and vascular physiology during spreading ii depolarization and its aftermath. The overall goal of these studies was to assess whether adenosine accumulates to a functionally relevant degree in brain tissue undergoing spreading depolarization. Initial studies utilized brain slices from mice, to evaluate adenosine accumulation and its contributions to the depression of synaptic activity accompanying SD. These studies revealed that adenosine-mediated effects were long-lasting, compared with an initial component explained by failure of action potentials during depolarization. Brain slices were also employed to inspect the behavior of cerebral blood vessels within brain tissue undergoing SD. Biphasic vasomotor responses were related to acute depolarization and the effects of metabolic demand, and adenosine appeared to contribute to this latter phase, in addition to other mediators. Subsequent in vivo studies found that adenosine accumulated as a consequence of SD in the brains of healthy mice with normal neurovascular coupling. Depolarization block and adenosine receptor activation were also found to contribute to the depression of spontaneous electrocortographic activity in vivo, in anesthetized mice. The degree of adenosine accumulation was enhanced when metabolic supply was limited, whether by hypoxia, hypoglycemia, or focal ischemic stroke. These studies established for the first time 1) that adenosine accumulates as a result of SD, 2) that adenosine is related to the degree of unmet metabolic demand during depolarization, 3) that neuronal and vascular adenosine receptor activation is relevant to spreading depression of activity and spreading hyperaemia accompanying SD. These findings represent significant progress in our understanding of the physiology of the brain and the pathophysiology of ischemic and traumatic brain injuries.

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

C. William Shuttleworth, Ph.D.

Second Committee Member

L. Donald Partridge, Ph.D.

Third Committee Member

Benjimen R. Walker, Ph.D.

Fourth Committee Member

C. Fernando Valenzuela, M.D., Ph.D.

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