The role of the ventrolateral medulla (VLM) and diaphragmatic afferents (DA) in the control of breathing under anesthesia remains controversial, and their role in unanesthetized conditions is even more speculative. Thus our objective is to test controversial hypotheses regarding the VLM and DA during physiologic conditions. For the VLM, we will study awake, anesthetized, and asleep goats using: 1) chronically implanted thermodes to cool (20 degrees) and thereby create reversible neuronal dysfunction at sites near the VLM surface, and 2) microinjections of kainic acid to create permanent neuronal dysfunction at discrete VLM sites. With cooling, dysfunction effects are not obscured by compensatory changes that may occur between studies before and after permanent lesions. With permanent lesions the nuclei underlying functions can be identified. Key hypotheses are: 1) Bilateral dysfunction of an area that includes the retrotrapezoid nucleus (RTN area) will cause apnea or hypoventilation during eucapnia; during several hyperpneic conditions it will not cause apnea but will uniformly attenuate breathing; 2) Bilateral dysfunction more caudally in the intermediate VLM (IVLM) will cause a general attenuation of breathing and respiratory muscle activity, but the attenuation will be greater during elevated CO2-H+ stimulation than during exercise, hypoxia, NaCN infusion, and ventilatory loading; and 3) Simultaneous dysfunction of both the RTN area and the IVLM after carotid chemoreceptor denervation will eliminate the CO2-H+ hyperpnea and cause prolonged apnea in anesthesia and NREM sleep. Testing these hypotheses will suggest whether: 1) the RTN is critical for generation of respiratory rhythm and whether it facilitates more dorsal medullary respiratory neurons, 2) the IVLM integrates or processes intracranial chemoreception and peripheral reflexes, 3) in all states, these VLM sites are critical for CO2-H+ ventilatory sensitivity, and 4) in anesthesia and NREM sleep breathing is critically dependent on the CO2-H+ stimulus and functional RTN and IVLM areas. For DA related objectives, we will study awake ponies. We hypothesize diaphragmatic deafferentation will: 1) reduce the increased stimulation of the diaphragm which occurs in a normal pony as that of reflexes known as operational length compensation and ventilatory load compensation; 2) eliminate this increased stimulation in a lung denervated pony. These findings will support the concept that DA contribute to these reflexes. Our studies will provide unique insights into the control of breathing during physiologic conditions and diseases such as Sudden Infant Death Syndrome, Ondine's Curse, sleep apnea, and COPD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Respiratory and Applied Physiology Study Section (RAP)
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Medical College of Wisconsin
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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
Martino, Paul F; Olesiak, S; Batuuka, D et al. (2014) Strain differences in pH-sensitive K+ channel-expressing cells in chemosensory and nonchemosensory brain stem nuclei. J Appl Physiol (1985) 117:848-56
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
Bonis, J M; Neumueller, S E; Krause, K L et al. (2013) Contributions of the Kölliker-Fuse nucleus to coordination of breathing and swallowing. Respir Physiol Neurobiol 189:10-21

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