Comprehensive Structural and Functional Mapping of the Mammalian Cardiac Nervous System

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ABSTRACT Cardiovascular diseases such as heart failure, arrhythmias, and hypertension are leading causes of morbidity and mortality in the United States and world-wide. The autonomic nervous system plays a critical role in the pathophysiology of these diseases and neuraxial modulation provides an important avenue for therapeutic intervention. The major goal of our research team is to precisely define the cardiac neural hierarchy and develop circuit diagrams from the macroscopic to cellular and molecular levels and share these data on an ongoing basis with the scientific community. This effort will also provide verified methods and tools for assessing neuromodulation. The research team will make them freely available to the scientific community. A multiscale, multidisciplinary approach across various species, highly relevant to human disease, will be used to define the anatomy of cardiac innervation in high definition. Neural structure will be linked to cardiac function. The complexity of cardiac neural control necessitates an integrative approach that will represent a tour de force in this field. State-of-the-art anatomical, physiological, and pharmacological approaches from `cells to man' must be combined in order to achieve the above goals. This approach will be utilized at each level of the neuraxis (heart, extracardiac intrathoracic neural structures and extrathoracic neural structures). The techniques proposed will allow, for the first time, a detailed description of the anatomical and molecular interactions at the synaptic and cell body levels in cardiac and extracardiac ganglia. The techniques used and the integration of these pathways represents the most innovative attempt to understand cardiac neural control ever undertaken. Understanding these pathways has the potential to accelerate development of therapies that will be able to precisely target neural structures and also guide methods to re-purpose already available therapies (e.g. nerve stimulators) for therapeutic purposes. Ultimately, these approaches are required to develop novel, effective, and affordable interventions for the management and prevention of heart disease and sudden cardiac death.