Interdependence among neuromodulators of ventilatory control

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DESCRIPTION (provided by applicant): Neurons within the respiratory network initiate and coordinate respiratory pump and airway muscle activation to adjust the level of pulmonary ventilation ( I) to maintain blood gas homeostasis. Chemoreceptors provide major excitatory drives to breathe (19, 22, 31, 65, 82), but it is the overall balance of excitatory and inhibitory neuromodulators that ultimately determine respiratory network excitability (15, 16, 28, 92). The contribution of endogenous neuromodulators to eupneic I while awake or asleep has not been determined, but in vitro evidence suggests "that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators" (16). The overall goal of our proposal is to test this hypothesis of neuromodulatory interdependence and test whether inadequate interdependence contributes to sleep disordered breathing (SDB) and/or opiate overdose-induced respiratory depression. In adult goats, microtubules will be chronically implanted for insertion into the preB¿tzinger Complex (preB¿tC) or hypoglossal motor nucleus (HMN) of probes for dialysis in mock cerebral spinal fluid (mCSF) of antagonists or agonist of excitatory or inhibitory neuromodulators during awake and asleep states. We will measure I, diaphragm and genioglossus (GG) muscle activity, and neurochemicals in effluent dialyzed mCSF. Specific Aim 1 determines whether there is interdependence among multiple excitatory neuromodulators within the preB¿tC. We hypothesize that: a) antagonists of muscarinic cholinergic, serotonin (5-HT2A), or neurokinin-1 receptors individually will have little or no effet on eupneic I and GG muscle activity but in combination will attenuate I and GG activity particularly during sleep and lead to SDB, b) antagonists of excitatory neuromodulatory inputs to the preB¿tC will produce compensatory changes in other neuromodulators at the site of antagonist dialysis. Specific Aim 2 determines whether there is interdependence within the preB¿tC between excitatory neuromodulators and the inhibitory neuromodulatory effects of ¿-opioid receptor activation. We hypothesize that: a) preB¿tC ¿-opioid receptor activation will depress I and GG activity while awake and to a greater extent during sleep, b) preB¿tC ¿-opioid receptor activation will not alter effluent neurochemical content and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors. Specific Aim 3 determines whether there is interdependence among neuromodulators of the HMN. We hypothesize that: a) unilateral dialysis of a ¿- opioid agonist within the HMN will decrease I and GG activity which during NREM and REM sleep will lead to SDB, b) there will be no compensatory changes in any of the measured local neurochemicals in the effluent mCSF during opioid dialysis, and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors.