Diabetes mellitus and aging are commonly associated with increased incidence and severity of cardiovascular diseases. However, our understanding of the neural mechanisms underlying these dysfunctions is impeded by a lack of structural information on autonomic nerve terminals and the circuitry within the cardiac tissues (brain-heart connections). Vagal projections to the heart originate from a sensory ganglion, i.e., the nodose ganglion, and the two motor nuclei, i.e., the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DmnX). The overall goal of the present application is to determine the functional deficits of the vagal control of the heart induced by diabetes, aging or both, and to identify the damage to the cardiac neural circuitry, specifically to the vagal axonal projections to the heart. Vagal control of particular cardiac functions will be measured in two murine models of type 1 diabetes (strepozotocin-treated and transgenic OVE 26 mice). The vagal cardiac axons and terminals, glutamatergic transmission, and oxygen reactive species (ROS) within the parasympathetic system will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing, stereological counting, confocal microscopy, Neurolucida digitization, multichannel injections, dual immunohistochemistry, and intercellular measurement of ROS. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships.
Aim 1 will assess diabetes-associated attenuation of baroreflex and vagal control of the heart, and the associated structural changes of vagal projections to the heart and aortic arch, and examine whether diabetes and aging interact to induce more severe functional and anatomical damage to the vagal cardiac axons.
Aim 2 will study diabetes and aging-associated changes in glutamatergic transmission within the brainstem.
Aim 3 will determine ROS productions in parasympathetic neurons in diabetic and aging mice, and study whether chronic antioxidant treatment may reduce/prevent cardiovascular dysfunctions and structural damages, Collectively, the proposed experiments will provide unique insights into the remodeling of vagal outflow to cardiac tissues following long-term diabetes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079636-04
Application #
7123381
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S1))
Program Officer
Rabadan-Diehl, Cristina
Project Start
2004-09-30
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$346,658
Indirect Cost
Name
University of Central Florida
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
150805653
City
Orlando
State
FL
Country
United States
Zip Code
32826
Lin, Min; Hatcher, Jeff T; Wurster, Robert D et al. (2014) Characteristics of single large-conductance Ca2+-activated K+ channels and their regulation of action potentials and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus. Am J Physiol Cell Physiol 306:C152-66
Li, Liang; Hatcher, Jeffrey T; Hoover, Donald B et al. (2014) Distribution and morphology of calcitonin gene-related peptide and substance P immunoreactive axons in the whole-mount atria of mice. Auton Neurosci 181:37-48
Lin, Min; Hatcher, Jeff T; Chen, Qing-Hui et al. (2011) Maternal diabetes increases large conductance Ca2+-activated K+ outward currents that alter action potential properties but do not contribute to attenuated excitability of parasympathetic cardiac motoneurons in the nucleus ambiguus of neonatal mice. Am J Physiol Regul Integr Comp Physiol 300:R1070-8
Lin, Min; Harden, Scott W; Li, Lihua et al. (2010) Impairment of baroreflex control of heart rate in conscious transgenic mice of type 1 diabetes (OVE26). Auton Neurosci 152:67-74
Lin, Min; Chen, Qing-Hui; Wurster, Robert D et al. (2010) Maternal diabetes increases small conductance Ca2+-activated K+ (SK) currents that alter action potential properties and excitability of cardiac motoneurons in the nucleus ambiguus. J Neurophysiol 104:2125-38
Li, Lihua; Huang, Chenghui; Ai, Jing et al. (2010) Structural remodeling of vagal afferent innervation of aortic arch and nucleus ambiguus (NA) projections to cardiac ganglia in a transgenic mouse model of type 1 diabetes (OVE26). J Comp Neurol 518:2771-93
Lin, Min; Hatcher, Jeff T; Chen, Qin-Hui et al. (2010) Small conductance Ca2+-activated K+ channels regulate firing properties and excitability in parasympathetic cardiac motoneurons in the nucleus ambiguus. Am J Physiol Cell Physiol 299:C1285-98
Lin, Min; Ai, Jing; Harden, Scott W et al. (2010) Impairment of baroreflex control of heart rate and structural changes of cardiac ganglia in conscious streptozotocin (STZ)-induced diabetic mice. Auton Neurosci 155:39-48
Gu, H; Zhang, Z-H; Epstein, P N et al. (2009) Impaired baroreflex control of renal sympathetic nerve activity in type 1 diabetic mice (OVE26). Neuroscience 161:78-85
Haaland, Wade C; Scaduto, Diane I; Maldonado, Mario R et al. (2009) A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome. Diabetes Care 32:873-7

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