Treatment of Sleep Disturbances in TBI with Orexin Receptor Antagonist

(1)退伍军人的TBI通常是一种慢性疾病，并产生长期的睡眠和行为障碍。 问题据报道，在TBI背景下，30-60%的TBI患者发生了脑损伤， 显著的发病率、日间认知问题和妨碍生活质量。本提案审查了 慢性TBI（CCI）小鼠模型中睡眠畸变和认知及行为障碍的影响。 神经ORX失调似乎是睡眠和行为障碍的一种机制，并提供了 用食欲素能药物治疗的机会。我们建议研究双重食欲素受体的作用， 拮抗剂治疗（DORA）对TBI小鼠模型中的睡眠、认知、焦虑和恐惧的影响。（二） 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， 焦虑，认知和其他行为通过广泛的神经投射。因为ORX系统 在TBI后LH的异常发展，ORX睡眠-觉醒中断被假设有助于慢性TBI。 睡眠和行为障碍。Lemborexant（LEM）是一种可商购的DORA， OX 1和OX 2受体，并改善人类原发性失眠症的睡眠潜伏期和维持， 动物模型LEM治疗被假设为逆转睡眠异常并改善认知， TBI造成的日间行为。(b)这项研究将如何推进生物医学知识-（c） 研究的意义以及它与优先领域的关系-这笔赠款代表了一个潜在的高- 失眠和其他行为障碍基于机制治疗的影响转化建议 慢性创伤性脑损伤这项由经验丰富的研究人员（卡普兰和Zielinski）提出的建议旨在探索新的研究 在以前没有得到资助的领域。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-如果LEM在睡眠方面的效用 干扰、焦虑和认知可以在拟议的SPiRE研究中得到证实，然后是更大规模的研究。 在动物中使用市售的DORA，然后可以追踪患有TBI的退伍军人。(3)预计 结果或产物-慢性CCI预计会产生睡眠异常，包括： 睡眠潜伏期和清醒发作，总睡眠时间和睡眠发作减少，REM和NREM干扰 睡眠和睡眠碎片。与载体相比，LEM被假设为逆转这些睡眠异常 治疗CCI预计会在NOR测试中产生记忆受损，通过降低的 探索LDTT任务，增加FC后的异常FR。预计登月舱会逆转这些行为 CCI组的损伤。CCI预计会导致LH中的ORX-A和-B水平降低， 与睡眠和行为障碍呈负相关。(4)方法和研究-我们 在雄性和雌性C57 BL/6小鼠中检查CCI与假CCI的模型。在目标1中，我们研究了 在CCI和假CCI中，在损伤后两个月， 通过睡眠qEEG的睡眠参数（睡眠潜伏期、觉醒时间、总睡眠、NREM和REM睡眠的测量 和delta EEG睡眠）。在目标2中，我们建议测量LEM单次和重复给药的影响， CCI使用NOR任务进行认知。我们在LDTT中检查LEM效应以测量运动行为， 探索新环境的焦虑。最后，我们在恐惧条件反射测试中测量LEM效应， 测量LEM对提示诱导的FR的影响。在目标1和2中，我们使用 免疫组化和检查ORX-A和ORX-B神经肽表达和行为之间的关系。

(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.