Several theories on the neural control of breathing that were based on data from reduced preparations were not supported by our recent findings in awake and asleep goats on the effects of rostral medullary neuronal dysfunction and/or carotid body denervation (CBD). Some findings mimicked the altered breathing found in obstructive sleep apnea (OSA) and congenital central hypoventilation syndrome (CCHS). The mechanisms that mediated these effects are not established, but one likely mechanism is through intracranial chemoreceptors for years thought to exist only near the ventral medullary surface (including the retrotrapezoid nucleus RTN)). However, findings in reduced preparations of chemoreceptors at widespread brain sites have raised questions related to the location and role of chemoreceptors that affect breathing in awake and asleep states and whether brain chemoreceptor sensitivity is altered by CBD. One recently identified site of chemoreception is the medullary raphe nuclei (MRN) whose role in the control of breathing during awake and asleep states remains speculative. Accordingly, to study chemosensitivity and the role of the RTN and MRN in the control of breathing, we will implant microtubules into these nuclei of goats to: a) create a focal acidosis by dialysis of mock cerebrospinal fluid with different PCO2's, or b) induce neuronal dysfunction through injection of glutamate or serotonin receptor antagonists or agonists, or a neurotoxin. Major hypotheses are: 1) focal acidosis (equivalent to that breathing 7 percent inspired CO2, delta brain pH approximately -.05) in the RTN will increase breathing in awake, but not asleep states, while acidosis in the MRN will increase breathing in asleep, but not awake states, 2) at RTN sites where focal acidosis increases breathing, neuronal dysfunction will attenuate whole body CO2 sensitivity, but not alter rest and exercise breathing, 3) neuronal dysfunction in the MRN will attenuate CO2 sensitivity and rest and exercise breathing, 4) during the first 10 days after CBD, the effect of RTN and MRN focal acidosis will be attenuated but 15 plus days after CBD, the effect of focal acidosis will be accentuated. and 5) at most RTN and MRN sites, the acute effects of neurotoxic lesions will be hypoventilation (rest and exercise) and attenuated CO2 sensitivity; the acute effects of these lesions will be greater in CBD than in intact goats, but recovery after lesioning will be greater in intact than in CBD goats. Our unique studies are important because hypotheses generated largely from reduced preparations will be tested in awake and asleep states to enhance the understanding of medullary chemoreceptor contribution to the control of breathing and how abnormalities in this contribution may underlie diseases such as OSA, CCHS, and the Sudden Infant Death Syndrome.
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