Long-term facilitation is a term used to define a sustained increase in respiratory motor activity that is observed for several hours following intermittent exposure to hypoxia (i.e. reduced oxygen levels). Our study is designed to determine whether or not the release of serotonin within or peripheral to the central nervous system is essential for initiating long-term facilitatin following a one-time exposure to intermittent hypoxia (IH) and following exposure to intermittent hypoxia each day for seven days. Once this is established in intact spontaneously breathing mice we will examine whether or not the release of serotonin within or peripheral to the central nervous system has role in the recovery of respiratory motor activity in spinal cord injured animals. To achieve our objectives we will investigate whether repeated exposure to intermittent hypoxia induces ventilatory long-term facilitation in intact mice or spinal cord injured mice with null mutation in the gene for tryptophan hydroxlyase that is neuron specific (TPH2 KO). Neurons in the brain and spinal cord of the TPH2 KO mice are void of tryptophan hydroxlyase and serotonin (brain or spinal cord), but peripheral serotonin is normal. Mice will be placed in a plethysmograph chamber to measure ventilation, frequency and tidal volume during IH. The mice will be placed in the chamber for 1 hour initially to become acclimated. Thereafter, ventilation will be measured for 15 minutes while the mice breathe room air. The mice will then be exposed to twelve 4-min episodes of 8 % oxygen/balance nitrogen. Each episode will be followed by a 4-min recovery period, with the exception of the recovery period that occurs after the last hypoxic episode which will be 90 minutes in duration. During the recovery periods the mice will breathe room air. The mice will be exposed daily to the intermittent hypoxia protocol for 10 days. Exposure will occur at the same time of day (i.e. 5 -7 am). Brief exposure to intermittent hypoxia each day over a number of weeks may result in a number of beneficial outcomes. This includes long-term facilitation of respiratory activity in upper airway muscles that could serve to mitigate breathing events in individuals with sleep apnea and the recovery of respiratory and limb motor function in spinal cord injured individuals. The results of our study may ultimately shift current clinical practice in regards to the target site and treatment for the recovery of motor function following spinal cord injury.

Public Health Relevance

Our study is relevant to public health because it may establish whether or not exposure to short episodes of hypoxia increase functional recovery of respiratory and motor limb function in spontaneously breathing spinal cord injured animals. Our study may also establish the mechanism and target site that mediates the link between exposure to hypoxia and recovery of motor function.

National Institute of Health (NIH)
Veterans Affairs (VA)
Veterans Administration (I21)
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John D Dingell VA Medical Center
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Komnenov, Dragana; Solarewicz, Julia Z; Afzal, Fareeza et al. (2016) Intermittent hypoxia promotes recovery of respiratory motor function in spinal cord-injured mice depleted of serotonin in the central nervous system. J Appl Physiol (1985) 121:545-57
Solarewicz, Julia Z; Angoa-Perez, Mariana; Kuhn, Donald M et al. (2015) The sleep-wake cycle and motor activity, but not temperature, are disrupted over the light-dark cycle in mice genetically depleted of serotonin. Am J Physiol Regul Integr Comp Physiol 308:R10-7
Hickner, Stephen; Hussain, Najaah; Angoa-Perez, Mariana et al. (2014) Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin. J Appl Physiol (1985) 116:240-50