Recently, the debate regarding respiratory rhythm and pattern generation has changed dramatically with the emergence of novel hypotheses that rhythm and pattern are generated by a state- and condition-dependent hybrid-network of brainstem respiratory neurons, or by dual medullary oscillators. One view of the latter is that a pre-Botzinger Complex (pre-BotzC) inspiratory and a para-facial (pFRG) expiratory rhythm generator are reciprocally coupled to mediate the alternate phases of the respiratory cycle with the pre-BotzC dominant during in vivo conditions. A second view is that pre-inspiratory neurons in the pFRG determine the respiratory rhythm. These novel hypotheses are based on data from neonatal and juvenile rats in in vitro or anesthetized preparations, and there is only conflicting indirect evidence as to whether there is a functional pFRG rhythm generator in adult mammals. Our in vivo physiologic preparation is ideally suited to address these controversies regarding intact network behavior. Accordingly, in our proposed studies, microtubules will be chronically implanted bilaterally into the pre-BotzC or pFRG of adult goats to inject agents while awake or asleep that will reversibly or irreversibly alter neuronal activity. Five hypotheses will be tested: 1) During awake and NREM sleep states, neurons within the pre- BotzC inhibit an expiratory muscle rhythm generator at another brainstem site, 2) During awake and NREM sleep states, an intact pFRG is required for activation of abdominal expiratory pump muscles and airway constrictor muscles, 3) After destruction of a medullary site critical for generation of the eupneic respiratory rhythm and pattern, there is plasticity within the respiratory control network to restore the eupneic rhythm and pattern, 4) Plasticity after chronic unilateral or bilateral destruction of the pre-BotzC or the pFRG is associated with a serotonin and neurotrophin mediated increased synaptic efficacy and increased neuronal activity at unlesioned rhythmogenic sites, and 5) Respiratory rhythm and pattern generating mechanisms are state and condition dependent. We will show that in adult mammals during awake room air conditions, both the pre-BotzC and the pFRG are required for the eupneic respiratory rhythm and the eupneic activation pattern of the pump and airway respiratory muscles. However the role of each site is not hardwired as lesions at either site will not uniformly alter rhythm and pattern over different conditions and states, and plasticity after lesioning one site will enable the other site to alone generate the eupneic rhythm and pattern. Our studies are particularly important because they directly pertain to conditions humans experience in their everyday lives, and because major respiratory diseases such as sleep apnea, sudden infant death, congenital central alveolar hypoventilation, and neurodegenerative disorders all are characterized by state related disorders of breathing. ? ? ?
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