Understanding the central nervous system mechanisms controlling breathing in mammals represents one of the fundamental challenges in contemporary respiratory physiology. Establishing neural mechanisms at the cellular and synaptic level remains a central problem in unraveling the nature and function of the respiratory control system. This proposal exploits the unique properties of in vitro preparations from the neonatal rat nervous system to study basic cellular and synaptic mechanisms. We have developed novel in vitro slice preparation of the neonatal rat brainstem that contain functionally active respiratory networks and provide unparalleled access to neuronal elements critical for generation and transmission of respiratory rhythm under conditions that are optimal for analysis of cellular and synaptic processes. We propose a set of closely interrelated projects whose specific aims are to determine: (1) basic neuronal substrates for generation and transmission of respiratory rhythm in the neonatal nervous system; (2) cellular and synaptic mechanisms of rhythm generation, (3) neurochemical and synaptic mechanisms for modulation of rhythm, and (4) dynamical properties of respiratory neurons and networks by computational methods. The long-range goal of this multidisciplinary set of projects is to explain the ontogeny and neurogenesis of respiratory rhythm and pattern in mammals in terms of the biophysical, synaptic and network properties of CNS respiratory neurons. Information to be obtained from this proposal is fundamental for understanding basic human physiology and pathologies where ventilatory failure results from dysfunction of CNS mechanisms controlling breathing, including such diseases as apnea of prematurity, congenital central hypoventilation, central alveolar hypoventilation, and sudden infant death syndrome.
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