Aging and the syndrome of obstructive sleep apnea, which is characterized by chronic intermittent hypoxia (CIH), are commonly associated with increased incidence and severity of hypertension, orthostatic intolerance, and 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. Vagal projections to the heart originate from a sensory ganglion, i.e., the nodose ganglion, and the motor neuron pools in the brainstem, 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 aging, CIH, 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 young (3months), middle age (12months) and aged (24 months) Fischer 344 rats. The vagal cardiac axons and terminals, and glutamatergic transmission within the NA and DmnX will be examined qualitatively and quantitatively using a battery of techniques that will include anterograde neural tracing, stereological counting, confocal microscopy, Neurolucida digitization, and dual immunohistochemistry. These anatomical findings will be assessed in conjunction with physiological responses to enhance our understanding of structure-function relationships.
Aim 1 will assess aging-associated attenuation of baroreflex and vagal control of the heart, and the associated structural changes of vagal projections to the heart and aortic arch.
Aim 2 will evaluate CIH-induced reduction of baroreflex sensitivity and vagal controls and the parallel vagal cardiac axon degeneration.
Aim2 will also determine whether aging and CIH interact to induce more severe functional and anatomical damage to the vagal cardiac axons.
Aim 3 will study changes in glutamatergic transmission within the caudal brainstem complex (NTS, NA, DmnX) during aging and following CIH. Collectively, the proposed experiments will advance our knowledge of brain-heart interactions and provide unique insights into the remodeling of vagal outflow to cardiac tissues during aging and following CIH.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
7R01AG021020-04
Application #
7211914
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Monjan, Andrew A
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2006-04-15
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$356,475
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
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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; 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
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; 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
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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
Ai, J; Wurster, R D; Harden, S W et al. (2009) Vagal afferent innervation and remodeling in the aortic arch of young-adult fischer 344 rats following chronic intermittent hypoxia. Neuroscience 164:658-66
Yan, Binbin; Li, Lihua; Harden, Scott W et al. (2009) Diabetes induces neural degeneration in nucleus ambiguus (NA) and attenuates heart rate control in OVE26 mice. Exp Neurol 220:34-43

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