Neural mechanisms underlying the connection between Neurotrauma and REM Sleep Behavior Disorder

神经创伤与快速眼动睡眠行为障碍之间联系的神经机制

• 批准号: 10589696
• 负责人: Miranda M Lim
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589696
• 关键词: Acceleration; Address; Amygdaloid structure; Animals; Behavior; Behavioral; Behavioral Symptoms; Binding; Botanical dietary supplements; Botanicals; Brain; Cerebrovascular Circulation; Clinical; Control Groups; Curcumin; Deposition; Development; Disease; Dreams; Electroencephalography; Electromyography; Exposure to; Extinction; Female; Fright; Functional disorder; Human; Image; Implant; Individual; Intervention; Knowledge; Methods; Middle East; Military Personnel; Modeling; Mus; Muscle Hypertonia; Muscle Tonus; Nerve Degeneration; Nervous System Trauma; Neural Pathways; Paralysed; Parkinson Disease; Parkinsonian Disorders; Patients; Pattern; Post-Traumatic Stress Disorders; Predisposition; Procedures; Process; REM Sleep; REM Sleep Behavior Disorder; Reporting; Risk; Severities; Skeletal Muscle; Sleep; Sleep disturbances; Stress; Symptoms; Testing; Transgenic Mice; Traumatic Brain Injury; Veterans; Violence; alpha synuclein; candidate identification; comorbidity; conditioned fear; controlled cortical impact; epidemiology study; gait examination; innovation; male; mouse model; neuromechanism; neuroprotection; pre-formed fibril; prevent; segregation; sleep abnormalities; synergism; synuclein; synucleinopathy; trauma exposure; ultrasound

Neurotrauma, including traumatic brain injury (TBI) and/or posttraumatic stress disorder (PTSD), is highly prevalent among US Veterans returning from military deployment, approximating upwards of 10-20% from recent conflicts in the Middle East. In addition to a myriad of disabling daytime symptoms, we and others have shown that neurotrauma is strongly associated with persistent and profound sleep disruption, in some cases lasting for decades. In particular, emerging evidence suggests that neurotrauma may disrupt normal inhibition of muscle tone during sleep. During rapid eye movement (REM) sleep, widespread paralysis of skeletal muscles normally occurs – a process that is dysregulated in REM sleep behavior disorder (RBD), characterized by violent dream enactment during REM sleep. We recently reported that RBD is increased by over two-fold in Veterans with comorbid TBI+PTSD, compared to Veterans without neurotrauma. The abnormal REM Sleep Without Atonia (RSWA) seen in patients with RBD is widely regarded as one of the earliest clinical manifestations of synucleinopathy, since 50-70% of patients with RBD eventually phenoconvert to Parkinson's Disease (PD) or related disorder. Emerging evidence from several epidemiological studies, including our own, have suggested that both TBI and PTSD synergize to increase risk of later development of PD. However, major gaps in our understanding remain. We still need to better understand the predictors and neural pathways by which neurotrauma leads to RBD and synucleinopathy among susceptible individuals, and we need to identify candidate therapies and windows for potential neuroprotective interventions in order to prevent phenoconversion. These gaps will be addressed in 3 aims. Aim 1 will determine the behavioral correlates of RSWA using a mouse model of combined TBI+PTSD. Using our previously established model of combined TBI+PTSD, mice will undergo controlled cortical impact and single prolonged stress procedures, followed by gait analysis, fear conditioning, and sleep electroencephalographic (EEG)/ electromyographic (EMG) recordings to quantify RSWA. Mice will then be segregated into 3 groups on the basis of trauma exposure and behavioral severity: Neurotrauma (NT), Trauma-Exposed (TE - behaviorally normal), and Controls (not exposed to trauma). In Aim 1, we hypothesize that mice in the NT group will show increased RSWA compared to TE and Controls, and the severity of behavioral symptoms will predict the degree of RSWA within the NT group. In Aim 2, we will determine brain functional connectivity underlying RSWA and behavioral deficits in mice with TBI+PTSD by using an innovative new method to image cerebral blood flow in live animals with functional ultrafast ultrasound (fUS). We hypothesize that mice in the NT group will show increased functional connectivity within the amygdala that will correlate with readouts of both behavior and RSWA. In Aim 3, we will determine how neurotrauma contributes to RSWA and synuclein dynamics in the SynGFP transgenic mouse, and test the ability of curcumin to slow this process. We will use the A53T SynGFP mouse, an established mouse model of accelerated synucleinopathy that closely mimics the human condition, in combination with our methods for TBI+PTSD and sleep recordings. We hypothesize that neurotrauma will accelerate alpha-synuclein deposition, and that curcumin will decrease alpha-synuclein burden and ameliorate behavioral deficits among NT mice. Results from these studies will provide valuable mechanistic information about the pathophysiology underlying neurotrauma's effects on REM sleep and synucleinopathy, as well as test a potentially promising treatment intervention. With this critical knowledge, we will take important steps forward in better predicting and mitigating potential neurodegeneration among Veterans with TBI/PTSD.

神经创伤，包括创伤性脑损伤（TBI）和/或创伤后应激障碍（PTSD），是高度危险的。 在从军事部署返回的美国退伍军人中普遍存在， 最近中东的冲突。除了无数的白天致残症状，我们和其他人有 在某些情况下，神经创伤与持续和严重的睡眠中断密切相关， 持续了几十年特别是，新出现的证据表明，神经创伤可能会破坏正常的抑制 肌肉张力的变化。在快速眼动（REM）睡眠期间，骨骼肌广泛麻痹， 肌肉正常发生-一个在REM睡眠行为障碍（RBD）中失调的过程， 在快速眼动睡眠期间以剧烈的梦境为特征。我们最近报告称，RBD增加了 与没有神经创伤的退伍军人相比，患有TBI+PTSD共病的退伍军人的死亡率增加了两倍以上。的 在RBD患者中观察到的无张力的异常REM睡眠（RSWA）被广泛认为是 突触核蛋白病的最早临床表现，因为50-70%的RBD患者最终表型转化 帕金森病（PD）或相关疾病。几项流行病学研究的新证据， 包括我们自己的研究表明，创伤性脑损伤和创伤后应激障碍协同作用，增加了以后发展为创伤性脑损伤的风险。 警局然而，我们的理解仍然存在重大差距。我们仍然需要更好地了解预测因素， 神经创伤导致易感个体中RBD和突触核蛋白病的神经通路，以及 我们需要确定候选疗法和潜在神经保护干预的窗口， 防止表型转化。这些差距将在三个目标中解决。目标1将决定行为 使用TBI+PTSD组合的小鼠模型，研究RSWA的相关性。利用我们先前建立的 结合TBI+PTSD，小鼠将经历受控的皮质撞击和单次延长的应激程序， 随后进行步态分析、恐惧条件反射和睡眠脑电图（EEG）/肌电图 (EMG)记录以量化RSWA。然后根据创伤将小鼠分成3组 暴露和行为严重程度：神经创伤（NT），创伤暴露（TE -行为正常），和 对照组（未暴露于创伤）。在目标1中，我们假设NT组的小鼠将表现出增加的 RSWA与TE和对照组相比，行为症状的严重程度将预测 NT组内的RSWA。在目标2中，我们将确定RSWA背后的大脑功能连接， TBI+PTSD小鼠的行为缺陷，通过使用创新的新方法对脑血流进行成像， 功能性超快超声（fUS）活体动物。我们假设NT组的小鼠会表现出 杏仁核内的功能连接增加，这将与行为和 RSWA。在目标3中，我们将确定神经创伤如何影响RSWA和突触核蛋白动力学。 SynGFP转基因小鼠，并测试姜黄素减缓这一过程的能力。我们将使用A53 T SynGFP 小鼠，一种已建立的加速性突触核蛋白病小鼠模型，非常模拟人类状况， 结合我们的创伤性脑损伤+创伤后应激障碍和睡眠记录的方法。我们假设神经创伤 加速α-突触核蛋白沉积，并且姜黄素将降低α-突触核蛋白负荷并改善 NT小鼠的行为缺陷。这些研究结果将提供有价值的机理信息 关于神经创伤对REM睡眠和突触核蛋白病影响的病理生理学，以及 测试一种潜在的有希望的治疗干预。有了这些重要的知识，我们将采取重要的步骤， 更好地预测和减轻TBI/PTSD退伍军人中潜在的神经退行性病变。