This grant will focus on determining the mechanisms underlying a form of activity-independent persistent changes in hypoglossal motoneurons in neonatal rats. We postulate that these mechanisms serve as a model for adaptive changes whose malfunction contributes to failures of respiratory plasticity, such as might underlie obstructive sleep apnea in humans. This work represents the convergence of three distinct aspects of brain function in mammals that are each of considerable importance in plasticity of the neural control of breathing: RESPIRATORY PLASTICITY- Changes in excitability of mammalian neurons lasting longer than a few minutes are the focus of considerable research. We will investigate a form of activity independent plasticity in a unique mammalian experimental system, a slice of brainstem from neonatal rodent that endogenously generates a rhythmic respiratory motor nerve output. We can therefore investigate mechanisms with all of the advantages of an in vitro system, yet in the context of the ongoing behavior. RESPIRATORY MOTONEURON FUNCTION - Motoneurons transform the internal actions of the brain into behavior, translating patterns of interneuronal activity into commands for skeletal muscle contraction and relaxation. How respiratory motoneurons respond to their inputs, and how their responses are regulated is basic to understanding how the brain maintains respiratory homeostasis. Motoneurons have the distinct advantage as model neurons in that their outputs are well-understood, i.e., muscle contraction, and in many cases, such as with inspiratory drive for breathing, their inputs are also well-understood. REGULATION OF BREATHING PATTERN-The mammalian brain is vigilant in control of breathing, regulating blood oxygen and carbon dioxide over a wide ranges of metabolism, posture and body movements, and compromises in muscle or cardiopulmonary function. Failure of the brain to maintain an appropriate motor output in humans suffering from disorders such as sleep apnea, apnea of prematurity, congenital central hypoventilation, central alveolar hypoventilation, and perhaps sudden infant death syndrome, leads to serious adverse health consequences, even death. If these pathologies are to be understood, the mechanisms controlling the output of respiratory motoneurons needs to be determined.
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