Respiratory Plasticity in TPH2 KO mice with spinal cord injury

描述 长期易化是一个术语，用于定义呼吸运动活动的持续增加，在间歇性暴露于缺氧（即氧气水平降低）后观察到数小时。我们的研究旨在确定在一次性暴露于间歇性缺氧（IH）和每天暴露于间歇性缺氧7天后，中枢神经系统内或外周5-羟色胺的释放是否对启动长期易化至关重要。一旦在完整的自主呼吸小鼠中建立了这一点，我们将检查中枢神经系统内或外周5-羟色胺的释放是否在脊髓损伤动物的呼吸运动活动恢复中起作用。为了实现我们的目标，我们将研究是否重复暴露于间歇性缺氧诱导性的长期促进在完整的小鼠或脊髓损伤的小鼠与无效突变的色氨酸羟化酶的基因是神经元特异性的（TPH 2 KO）。TPH 2 KO小鼠的脑和脊髓中的神经元没有色氨酸羟化酶和5-羟色胺（脑或脊髓），但外周5-羟色胺是正常的。将小鼠置于体积描记器室中以测量IH期间的通气量、频率和潮气量。最初将小鼠置于室内1小时以适应环境。此后，在小鼠呼吸室内空气的同时测量通气量15分钟。然后将小鼠暴露于12次4分钟的8%氧气/平衡氮气的事件。每次缺氧发作后将有4分钟的恢复期，但最后一次缺氧发作后的恢复期除外，恢复期将持续90分钟。在恢复期间，小鼠将呼吸室内空气。小鼠将每天暴露于间歇性缺氧方案， 10天暴露将在一天中的同一时间进行（即上午5 - 7点）。每天短暂暴露于间歇性缺氧几周可能会导致一些有益的结果。这包括长期促进上气道肌肉的呼吸活动， 可以用于减轻患有睡眠呼吸暂停的个体的呼吸事件和脊髓损伤个体的呼吸和肢体运动功能的恢复。我们的研究结果可能最终改变目前关于脊髓损伤后运动功能恢复的靶点和治疗的临床实践。

DESCRIPTION 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.