The long range goal of our laboratory is to understand the cellular, synaptic and network properties that underlie the nervous system control of breathing in mammals. An important component of this problem is determining processes that regulate neuronal excitability. As the processes that regulate and modulate the excitability of single neurons in mammals are increasingly revealed, it is a major challenge to determine their role in functionally identifiable neurons participating in meaningful actions. Understanding how any single neuron or class of neurons participates in any complex behavior requires studying those neurons in the context of that behavior. How is centrally generated respiratory rhythm transformed into a meaningful and efficient pattern of motoneuronal activity? We propose to address this problem by studying the mechanisms acting the excitability of phrenic motoneurons. These motoneurons innervate the diaphragm, the main inspiratory muscle. Given the necessity that breathing be appropriate for blood-gas regulation, efficient and integrated into other body functions, such as locomotion and posture, and the other roles of the diaphragm (e.g., vocalization,defecation), the precise regulation of phrenic motoneuronal output is critical. We have an ideal system for understanding the role of identified cellular and synaptic properties in controlling neuronal excitability since: (i) the function of phrenic motoneurons is known; (ii) their main inputs with respect to breathing are known both functionally and anatomically; (iii) measurements can be made in these cells while the nervous system is generating rhythmic respiratory-related activity. We propose to study the modulation of phrenic motoneuronal excitability by: l. Testing the role of specific EAA receptor properties, such as desensitization and glycine modulation of the NMDA receptor, on inspiratory drive potentials and currents. 2. Testing the hypothesis that there is modulation by a presynaptic autoreceptor and a presynaptic 5-HT receptor on neurons transmitting inspiratory drive. 3. Determining the action of neuromodulators on phrenic motoneuronal excitability. The excitability of all neurons is subject to modulation. Our unique advantage of making measurements in the context of behavior may reveal the most critical elements underlying control of excitability and its modulation in the normal transactions of the intact living brain. There are many diseases of breathing, such as sleep apnea, sudden infant death syndrome, central alveolar hyperventilation, central inspiratory muscle fatigue for which rational therapies require a deeper understanding of the underlying neural mechanisms. Therapeutic and abusive drugs that affect breathing, such as anesthetics or heroin, typically produce their effects by pharmacologically specific deficits, and may be ameliorated by pharmacological manipulation. Understanding the synaptic physiology and pharmacology of the control of breathing is essential for further development of treatments.
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