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)目的-退伍军人的脑损伤通常是一种慢性疾病，会产生长期的睡眠和行为 有问题。据报道，30%-60%的人在脑损伤后出现失眠，并产生 严重的发病率、日间认知问题并阻碍生活质量。这份提案审查了 睡眠异常以及认知和行为障碍对慢性脑损伤小鼠模型的影响。 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 用食欲素能药物治疗的机会。我们建议研究双重增食欲素受体的作用。 拮抗剂治疗(DORA)对脑外伤小鼠睡眠、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产生焦虑、认知和其他行为。因为ORX系统 颅脑损伤后黄体生成素的异常发展，或睡眠-觉醒中断被认为与慢性脑损伤有关 睡眠和行为障碍。LEmplrexant(LEM)是一种商业化的Dora，可以阻断增食欲素 OX1和OX2受体并改善原发性失眠的睡眠潜伏期和维持性 动物模型。LEM治疗被认为是为了扭转睡眠异常，改善认知和 由TBI产生的日间行为。(B)这项研究将如何促进生物医学知识--(C) 研究的意义及其与优先领域的关系--这笔赠款代表着潜在的高- 基于机制治疗失眠和其他行为障碍的Impact翻译建议 慢性脑外伤。这项由经验丰富的研究人员(卡普兰和齐林斯基)提出的建议旨在探索新的研究 在他们以前没有得到资助的领域。因此，它作为TBI小型项目响应RX-20-009 康复研究(SPIRE)。(D)直接效益和服务质量--如果LEM对睡眠的效用 不安、焦虑和认知可以在提议的SPIRE研究中得到证明，然后是更大规模的研究 在动物身上使用商业上可用的DORA，然后在患有脑损伤的退伍军人身上进行研究。(3)预期 结果或产物-慢性CCI预计会导致睡眠异常，包括：增加 睡眠潜伏期和觉醒次数减少，总睡眠时间和睡眠次数减少，REM和NREM障碍 睡眠，以及睡眠的碎片化。与车辆相比，LEM被认为是为了扭转这些睡眠异常 治疗。CCI预计会在NOR测试中产生记忆力受损，通过减少来衡量更大的焦虑 探索LDTT任务，增加FC后的异常FR。预计LEM会逆转这些行为 CCI组的损害。CCI有望降低黄体生成素的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 在雄性和雌性C57BL/6小鼠身上检测CCI模型和假CCI模型。在目标1中，我们考察了 单次和多次给予LEM(0，10，30，mg/kg)对CCI和Sham CCI在损伤后2个月的影响 通过睡眠qEEG获得的睡眠参数(测量睡眠潜伏期、觉醒时间、总睡眠、非快速眼动睡眠和快速眼动睡眠 和增量脑电睡眠)。在目标2中，我们建议测量LEM的单次和重复剂量效应 使用NOR任务的认知CCI。我们在LDTT中检查LEM效应以测量运动行为和 探索新环境时的焦虑。最后，我们在恐惧条件反射测试中测量LEM效应 测量LEM对线索诱导的FR的影响。在目标1和目标2中，我们使用以下方法测量黄体生成素水平 并检测ORX-A和ORX-B神经肽表达与行为之间的关系。