Treatment of Sleep Disturbances in TBI with Orexin Receptor Antagonist

食欲素受体拮抗剂治疗 TBI 睡眠障碍

• 批准号: 10248584
• 负责人: Gary B. Kaplan
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248584
• 关键词: Affect; Afghanistan; Animal Model; Animals; Anxiety; Area; Arousal; Behavior; Behavioral; Brain; Brain Injuries; C57BL/6 Mouse; Cells; Cerebrospinal Fluid; Chronic; Chronic Disease; Cognition; Cognitive; Cues; Dose; Electroencephalogram; Emotional Disturbance; Environment; Female; Fright; Funding; Grant; Health; Human; Hypothalamic structure; Impaired cognition; Individual; Injury; Iraq; Knowledge; Lead; Lesion; Light; Maintenance; Measures; Mediating; Memory; Memory Loss; Memory impairment; Modeling; Morbidity - disease rate; Mus; Neurons; Neuropeptides; Neurophysiology - biologic function; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Post-Traumatic Stress Disorders; Primary Insomnia; Problem behavior; Quality of life; REM Sleep; Reporting; Research; Research Personnel; Rewards; Rodent; Rodent Model; Services; Sleep; Sleep Disorders; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Symptoms; System; TBI Patients; Testing; Time; Veterans; War; awake; base; behavior test; behavioral impairment; behavioral response; cholinergic; conditioned fear; dopaminergic neuron; experience; experimental group; falls; human model; hypocretin; improved; male; motor behavior; mouse model; neural circuit; neuropeptide B; non rapid eye movement; noradrenergic; novel; orexin A; orexin B; receptor; rehabilitation research; relating to nervous system; sleep abnormalities; sleep onset; symptomatology; translational impact; treatment effect; wound

(1) PURPOSE- TBI in Veterans can often be a chronic condition and produce long-term sleep and behavioral problems. Insomnia in the context of TBI is reported in 30–60% of individuals following TBI and produces significant morbidity, daytime cognitive problems and impedes the quality of life. This proposal examines the impact of sleep aberrations and cognitive and behavioral disturbances in a mouse model of chronic TBI (CCI). Neural ORX dysregulation appears to be a mechanism for sleep and behavioral disturbances and provides an opportunity to treat with orexinergic agents. We propose to examine the effects of a dual orexin receptor antagonist treatment (DORA) on sleep, cognition, anxiety, and fearfulness in a mouse model of TBI. (2) BACKGROUND- (a) Scientific Rationale- ORX activates neural circuits by regulating awake state and arousal, anxiety, cognition, and other behaviors through widespread neural projections. Because ORX system abnormalities in the LH develop after TBI, ORX sleep-wake disruptions are hypothesized to contribute to chronic sleep and behavioral disturbances. Lemborexant (LEM) is a commercially available DORA that blocks orexin OX1 and OX2 receptors and improves sleep latency and maintenance in primary insomnia in both humans and animal models. LEM treatment is hypothesized to reverse sleep abnormalities and improve cognition and daytime behaviors produced by TBI. (b) How This Research Will Advance Biomedical Knowledge- (c) Significance of the Research and How it Relates to Priority Areas – This grant represents a potential high- impact translational proposal for a mechanism-based treatment for insomnia and other behavioral disturbances in chronic TBI. This proposal by experienced investigators (Kaplan and Zielinski) seeks to explore new research in areas where they have not previously been funded. As such, it responds to RX-20-009 as a TBI Small Project in Rehabilitation Research (SPiRE). (d) Direct Benefits and Quality of Services- If the utility of LEM on sleep disturbances, anxiety, and cognition can be demonstrated in proposed SPiRE studies, then larger scale studies using commercially available DORAs in animals and then Veterans with TBI can be pursued. (3) EXPECTED OUTCOMES OR PRODUCTS– Chronic CCI is anticipated to produce sleep abnormalities including: increased sleep latency and wake bouts, reduced total sleep time and sleeping bouts, disturbances of REM and NREM sleep, and sleep fragmentation. LEM is hypothesized to reverse these sleep abnormalities compared to vehicle treatment. CCI is expected to produce impaired memory in NOR test, greater anxiety as measured by decreased exploration in LDTT task and increase aberrant FR after FC. It is expected that LEM reverses these behavioral impairments in the CCI group. CCI is expected to produce reductions of ORX-A and -B levels in LH that are inversely correlated with sleep and behavioral disturbances. (4) METHODS AND RESEARCH PLAN- We examine a model of CCI vs. sham CCI in male and female C57BL/6 mice. In Aim 1, we examine the effects of single- and repeated-dose effects LEM (0, 10, 30, mg/kg) in CCI and sham CCI, at two months post-injury, on sleep parameters via sleep qEEG (measures of sleep latency, wake time, total sleep, NREM and REM sleep and delta EEG sleep). In Aim 2, we propose to measure the effects of single- and repeated-dose effects LEM in CCI on cognition using the NOR task. We examine LEM effects in the LDTT to measure motor behavior and anxiety in exploring a novel environment. Finally, we measure LEM effects in a fear conditioning test and measure LEM effects on with cue-induced FR. In Aims 1 and 2, we measure ORX-A and -B levels in LH using IHC and examine relationships between ORX-A and ORX-B neuropeptide expression and behaviors.

（1）退伍军人中的目的通常是慢性病，并产生长期睡眠和行为 问题。在TBI之后，有30-60％的个体报告了TBI的失眠症，并产生 明显的发病率，白天的认知问题并阻碍了生活质量。该提案考试 慢性TBI小鼠模型（CCI）的睡眠畸变以及认知和行为障碍的影响。 神经ORX失调似乎是睡眠和行为灾难的机制，并提供了 与Orexinagic剂治疗的机会。我们建议检查双奥甲蛋白接收器的效果 TBI小鼠模型中有关睡眠，认知，动画和恐惧的拮抗剂治疗（DORA）。 （2） 背景 - （a）科学理由 - ORX通过调节清醒状态和唤醒来激活神经回路 通过宽度神经项目的焦虑，认知和其他行为。因为ORX系统 TBI后LH的异常发生，ORX睡眠效果干扰被认为有助于慢性 睡眠和行为干扰。 Lemborexant（LEM）是一种可堵塞Orexin的市售多拉 OX1和OX2受体并改善了人类和原发性失眠的睡眠潜伏期和维持 动物模型。假设LEM治疗以逆转睡眠异常并改善认知和 TBI产生的白天行为。 （b）这项研究将如何提高生物医学知识 - （c） 研究的意义及其与优先领域的关系 - 该赠款代表了潜在的高 对基于机制的失眠和其他行为灾难的治疗的影响翻译建议 在慢性TBI中。经验丰富的研究人员（Kaplan和Zielinski）提出的这一提议旨在探索新的研究 在以前没有资助的地区。因此，它响应RX-20-009作为TBI小型项目 在康复研究（Spire）中。 （d）直接利益和服务质量 - 如果LEM在睡眠中的实用性 在拟议的尖峰研究中可以证明障碍，动画和认知，然后进行大规模研究 可以在动物中使用市售的多拉斯，然后可以追捕具有TBI的退伍军人。 （3）期望 结果或产品 - 预计慢性CCI会产生睡眠异常，包括：增加 睡眠潜伏期和唤醒，减少了总睡眠时间和睡眠回合，REM和NREM的灾难 睡眠和睡眠破碎。假设LEM与车辆相比扭转了这些睡眠异常 治疗。预计CCI在NOR测试中会产生不良记忆力，如有改善来衡量 LDTT任务中的探索，并在FC后增加异常FR。预计LEM会逆转这些行为 CCI组的障碍。预计CCI将在LH中降低ORX -A和-b水平 与睡眠和行为灾难成反比。 （4）方法和研究计划 - 我们 检查男性和雌性C57BL/6小鼠中CCI与Sham CCI的模型。在AIM 1中，我们研究了 CCI和SHAM CCI的单剂量和重复剂量LEM（0、10、30，mg/kg）在受伤后两个月，在 睡眠参数通过睡眠qeeg（睡眠潜伏期，唤醒时间，全部睡眠，NREM和REM睡眠 和三角洲脑电睡眠）。在AIM 2中，我们建议测量单剂量和重复剂量效应在 CCI使用NOR任务进行认知。我们检查LDTT中的LEM效应，以测量运动行为和 探索新型环境时的焦虑。最后，我们在恐惧调节测试和 用提示诱导的FR测量LEM效应。在AIMS 1和2中，我们使用LH测量ORX -A和-b级别 IHC并检查ORX-A和ORX-B神经肽表达和行为之间的关系。