Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

12-2008

Committee Chair or Co-Chairs

Donald B. Hoover

Committee Members

Michelle M. Duffourc, Krishna Singh, Jeffrey L. Ardell, Carole A. Williams

Abstract

Murine models have become increasingly popular to study various aspects of cardiovascular diseases due to their ease of genetic manipulation. Unfortunately, there has been little effort put into describing the distribution of autonomic nerves in the mouse heart, making it difficult to compare current findings from clinical and experimental models related to cardiovascular diseases. Furthermore, determination of the requirements for the development of this system and its maintenance in adult mice remains largely unexplored. This study represents the first detailed mapping of cholinergic neuroanatomy of the mouse heart based on immunohistochemical staining using true cholinergic markers. We found cholinergic innervation of the mouse heart to be largely focused in the atrium and conducting system. We investigated the involvement of the neurotrophic factor neurturin (NRTN) in the development of cholinergic innervation, because there was indirect evidence that implicated it as a crucial factor. Results from our work definitively demonstrate that NRTN plays a major role in the development of cardiac parasympathetic ganglia and cholinergic innervation of the mouse heart. Adult NRTN knockout mice exhibited a drastic reduction in the number of intracardiac neurons with decreased atrial acetylcholine, cholinergic nerve density at the sinoatrial node and negative chronotropic responses to vagal stimulation. The presence of NRTN and its receptors in hearts from adult wild-type mice suggests that this neurotrophic factor might also be required for maintenance of cardiac cholinergic innervation. Finally, we wanted to determine how intracardiac neurons and their processes change during diseased states, specifically type 1 diabetes. This work has shown that the cardiac cholinergic nervous system in the mouse undergoes structural and functional remodeling when challenged with streptozotocin-induced diabetes. Cholinergic nerves in diabetic hearts undergo extensive sprouting at the sinoatrial node with no change in the number of intracardiac neurons. Cholinergic function appears to be enhanced in diabetic mice, based on pharmacological testing, despite decreased response to direct vagal nerve stimulation. Evidence also suggests that diabetic mice have an imbalance in autonomic control of heart rate. The latter findings suggest that disruption of central input into intrinsic cardiac ganglia also contributes to the neuropathology of type 1 diabetes.

Document Type

Dissertation - Open Access

Copyright

Copyright by the authors.

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