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.
A major objective of our proposed studies on the control of breathing is to determine if reductions in the stimulation of cells in the lower part of the brain cause breathing to stop (apnea) as occurs in many humans during sleep or drug overdose. A second objective is to determine if reducing one or more stimulatory factor is compensated by increased level of another stimulatory factor. These studies relate specifically to breathing problems during sleep and problems caused by substances used to manage pain.
|Langer 3rd, Thomas M; Neumueller, Suzanne E; Crumley, Emma et al. (2017) Ventilation and neurochemical changes during µ-opioid receptor activation or blockade of excitatory receptors in the hypoglossal motor nucleus of goats. J Appl Physiol (1985) 123:1532-1544|
|Langer 3rd, Thomas M; Neumueller, Suzanne E; Crumley, Emma et al. (2017) State-dependent and -independent effects of dialyzing excitatory neuromodulator receptor antagonists into the ventral respiratory column. J Appl Physiol (1985) 122:327-338|
|Langer 3rd, Thomas M; Neumueller, Suzanne E; Crumley, Emma et al. (2017) Effects on breathing of agonists to ?-opioid or GABAA receptors dialyzed into the ventral respiratory column of awake and sleeping goats. Respir Physiol Neurobiol 239:10-25|
|Muere, Clarissa; Neumueller, Suzanne; Olesiak, Samantha et al. (2015) Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats. J Appl Physiol (1985) 119:308-20|
|Muere, Clarissa; Neumueller, Suzanne; Miller, Justin et al. (2015) Evidence for respiratory neuromodulator interdependence after cholinergic disruption in the ventral respiratory column. Respir Physiol Neurobiol 205:7-15|
|Muere, Clarissa; Neumueller, Suzanne; Olesiak, Samantha et al. (2015) Blockade of neurokinin-1 receptors in the ventral respiratory column does not affect breathing but alters neurochemical release. J Appl Physiol (1985) 118:732-41|
|Forster, Hubert; Bonis, Josh; Krause, Katie et al. (2014) Contributions of the pre-Bötzinger complex and the Kölliker-fuse nuclei to respiratory rhythm and pattern generation in awake and sleeping goats. Prog Brain Res 209:73-89|
|Miller, Justin Robert; Neumueller, Suzanne; Muere, Clarissa et al. (2014) Changes in glutamate receptor subunits within the medulla in goats after section of the carotid sinus nerves. J Appl Physiol (1985) 116:1531-42|
|Muere, Clarissa; Neumueller, Suzanne; Miller, Justin et al. (2013) Atropine microdialysis within or near the pre-Botzinger Complex increases breathing frequency more during wakefulness than during NREM sleep. J Appl Physiol (1985) 114:694-704|
|Miller, Justin Robert; Neumueller, Suzanne; Muere, Clarissa et al. (2013) Changes in neurochemicals within the ventrolateral medullary respiratory column in awake goats after carotid body denervation. J Appl Physiol (1985) 115:1088-98|