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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

基本信息

批准号：
10447665
负责人：
Mark Robert Zielinski
金额：
--
依托单位：
VA BOSTON HEALTH CARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447665
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 antagonist 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

项目摘要

(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) 目的——退伍军人的 TBI 通常可能是一种慢性疾病，并会导致长期睡眠和行为问题。据报道，30-60% 的 TBI 患者会因 TBI 而失眠，并产生失眠症状严重的发病率、日间认知问题并影响生活质量。该提案审查了慢性 TBI (CCI) 小鼠模型中睡眠异常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障碍的一种机制，并提供了一种有机会用食欲素药物治疗。我们建议检查双重食欲素受体的作用拮抗剂治疗（DORA）对 TBI 小鼠模型睡眠、认知、焦虑和恐惧的影响。 (2) 背景- (a) 科学原理- ORX 通过调节清醒状态和唤醒来激活神经回路，通过广泛的神经投射来控制焦虑、认知和其他行为。因为ORX系统 TBI 后 LH 出现异常，ORX 睡眠-觉醒中断被认为会导致慢性睡眠和行为障碍。 Lemborexant (LEM) 是一种市售 DORA，可阻断食欲素 OX1 和 OX2 受体并改善人类和原发性失眠症的睡眠潜伏期和维持动物模型。 LEM 治疗被认为可以逆转睡眠异常并改善认知能力和 TBI 产生的白天行为。 (b) 这项研究将如何推进生物医学知识 - (c) 研究的意义及其与优先领域的关系——这项资助代表了潜在的高基于机制治疗失眠和其他行为障碍的影响转化提案在慢性 TBI 中。这项由经验丰富的研究人员（Kaplan 和 Zielinski）提出的提案旨在探索新的研究在以前没有获得资助的领域。因此，它响应 RX-20-009 作为 TBI 小型项目康复研究（SPiRE）。 (d) 直接效益和服务质量 - LEM 对睡眠的效用干扰、焦虑和认知可以在拟议的 SPiRE 研究中得到证明，然后进行更大规模的研究在动物身上使用市售的 DORA，然后可以追踪患有 TBI 的退伍军人。 (3) 预期结果或产品——慢性 CCI 预计会产生睡眠异常，包括：睡眠潜伏期和觉醒发作、总睡眠时间和睡眠发作减少、快速眼动 (REM) 和非快速眼动 (NREM) 干扰睡眠，以及睡眠碎片。与车辆相比，LEM 被认为可以逆转这些睡眠异常治疗。 CCI 预计会在 NOR 测试中产生记忆受损，通过减少测量来衡量更大的焦虑探索LDTT任务并增加FC后的异常FR。预计 LEM 会扭转这些行为 CCI 组的损伤。 CCI 预计会降低 LH 中的 ORX-A 和 -B 水平，与睡眠和行为障碍呈负相关。 (4) 方法和研究计划-我们检查雄性和雌性 C57BL/6 小鼠的 CCI 模型与假 CCI 模型。在目标 1 中，我们检查了以下因素的影响：损伤后两个月，LEM（0、10、30 mg/kg）对 CCI 和假 CCI 的单次和重复剂量影响通过睡眠 qEEG 获取睡眠参数（测量睡眠潜伏期、唤醒时间、总睡眠时间、NREM 和 REM 睡眠）和 Delta 脑电图睡眠）。在目标 2 中，我们建议测量单次和重复剂量 LEM 的效果 CCI 使用 NOR 任务进行认知。我们检查 LDTT 中的 LEM 效应来测量运动行为并探索新环境时的焦虑。最后，我们在恐惧调节测试中测量 LEM 效果，测量 LEM 对提示诱导 FR 的影响。在目标 1 和 2 中，我们使用以下方法测量 LH 中的 ORX-A 和 -B 水平： IHC 并检查 ORX-A 和 ORX-B 神经肽表达和行为之间的关系。