Respiratory Plasticity in TPH2 KO mice with spinal cord injury

脊髓损伤 TPH2 KO 小鼠的呼吸可塑性

• 批准号: 8633116
• 负责人: Jason H. Mateika
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633116
• 关键词: Address; Air; Anatomic Sites; Animals; Brain; Breathing; Cell Nucleus; Environmental air flow; Event; Exposure to; Frequencies; Generations; Genes; Hour; Human; Hypoxia; Individual; Lead; Limb structure; Link; Measures; Mediating; Methysergide; Motor; Motor Activity; Motor Neurons; Mus; Muscle; Neuraxis; Neuromodulator; Neurons; Outcome; Oxygen; Paralysed; Peripheral; Play; Preparation; Protocols documentation; Public Health; Recovery; Recovery of Function; Reporting; Respiratory physiology; Role; Series; Serotonin; Signal Transduction; Site; Sleep; Sleep Apnea Syndromes; Source; Spinal Cord; Spinal cord injury; Structure; TDO2 gene; Tidal Volume; Time; Tryptophan; Wakefulness; Wild Type Mouse; afferent nerve; base; clinical practice; design; motor function recovery; nitrogen balance; null mutation; public health relevance; raphe nuclei; receptor; relating to nervous system; respiratory; response; treatment site

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.

描述 长期促进是一种用于定义呼吸运动活动持续增加的术语，在间歇性暴露于缺氧后几个小时（即氧气降低）观察到。我们的研究旨在确定在一次性间歇性缺氧（IH）一次性接触后，在每天一次接触间歇性缺氧后，在中枢神经系统内释放或中枢神经系统中是否释放了中枢神经系统至关重要。一旦在完整的自发呼吸小鼠中确定了这一点，我们将检查中枢神经系统内或周围释放5-羟色胺在脊髓损伤动物中的呼吸运动活动中的作用。为了实现我们的目标，我们将调查反复暴露于间歇性缺氧是否会导致完整小鼠的通气长期促进或脊髓损伤的小鼠，而在基因中，基因的无效突变是神经元特异性（TPH2 KO）的色氨酸羟基酶。 TPH2 KO小鼠的大脑和脊髓中的神经元无氧和5-羟色胺（脑或脊髓）无效，但外周羟色胺正常。小鼠将放置在散布的室内，以测量IH期间的通风，频率和潮汐体积。老鼠最初将放置在房间中1小时以适应。此后，在鼠标呼吸房间空气时，将测量通风15分钟。然后，小鼠将暴露于8％氧/平衡氮的十二个4分钟发作。每个情节都将是一个4分钟的恢复期，除了最后一次缺氧发作之后发生的恢复期，持续时间为90分钟。在恢复期间，老鼠将呼吸空气。小鼠将每天暴露于间歇性的缺氧方案 10天。暴露将在一天中的同一时间（即5 -7 AM）发生。每天在数周内短暂暴露于间歇性缺氧可能会导致许多有益的结果。这包括长期促进上呼吸道肌肉中的呼吸道活动 可以减轻睡眠呼吸暂停患者的呼吸事件以及脊髓受伤个体呼吸和肢体运动功能的恢复。我们研究的结果最终可能会改变有关目标部位的当前临床实践，并在脊髓损伤后恢复运动功能的治疗方法。