Author ORCID Identifier

https://orcid.org/0000-0001-7153-9028

Date of Graduation

12-2017

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Dr. Louise McCullough M.D., Ph.D.

Committee Member

Dr. Shane Cunha Ph.D.

Committee Member

Dr. Jarek Aronowski Ph.D.

Committee Member

Dr. Robery Bryan Ph.D.

Committee Member

Dr. Daniel Mulkey Ph.D.

Committee Member

Dr. Andrew Bean Ph.D.

Abstract

Modeling Post Stroke Respiratory Dysfunction,

Apneas and Cognitive Decline

Anthony Patrizz, B.A.

Advisory Professor: Louise McCullough M.D., Ph.D.

Stroke is a major cause of mortality and the leading cause of long-term disability in the US. More than 60% of individuals suffering a first time stroke develop respiratory dysfunction, prolonging recovery and increasing mortality. Post-stroke cognitive decline is a major contributor to disability and nursing home placement, therefore the cognitive consequences of Stroke Induced Respiratory Dysfunction (SIRD) need to be explored if we hope to enhance functional recovery. The first step towards treatment of the negative consequences of SIRD is the development of appropriate animal models that will allow us to explore the pathophysiology of SIRD and provide the opportunity to test potential pharmacological agents.

We developed and characterized an animal model of stroke induced respiratory dysfunction recapitulating the respiratory phenotype witnessed in the clinical population, characterized by incidences of apnea and hypoventilation. Interestingly, mice with high incidence of apneas display signs of progressive cognitive decline compared to those with low/no incidence of apneas. Histological analysis of vital brainstem respiratory control sites unveiled reactive astrocytosis, an important cell type in the neurovascular unit and an essential component of chemoreception. Respiratory dysfunction and brainstem astrocytosis was reproduced in mice that underwent intracerebroventricular injections of TGF-b. Suggesting the TGF-b signaling pathway contributes to the onset of astrogliosis and respiratory dysfunction.

Our data suggests that stroke disrupts basal breathing rather than increasing chemoreceptor gain. Therefore, we predict treatments designed to stimulate breathing independent of chemoreceptor gain will improve respiratory instability, behavior, cognition and mortality. Systemic application of acetazolamide eliminated apneas while preventing further cognitive decline.

This work not only developed a model of stroke induced respiratory dysfunction that recapitulates the respiratory phenotype witnessed in the clinical population, but also providing translational relevance to the field of stroke, aging, and cognitive decline. Successful treatment of SIRD may lead to significant improvements in post-stroke recovery and cognition.

Keywords

stroke, disordered breathing, apnea, cognitive decline

Available for download on Friday, June 15, 2018

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