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.

神经瘤，包括创伤性脑损伤（TBI）和/或创伤后应激障碍（PTSD），高度高度 在美国退伍军人中，从军事部署返回，大约超过10-20％ 最近在中东发生的冲突。除了无数的白天症状外，我们和其他人都有 表明Neurotrauma与持续和深刻的睡眠中断密切相关，在某些情况下 持续数十年。特别是，新兴的证据表明神经突可能破坏正常抑制 睡眠期间的肌肉音。在快速眼动（REM）睡眠期间，骨骼的宽度瘫痪 肌肉通常发生 - 在REM睡眠行为障碍（RBD）中失调的过程， 在REM睡眠期间以暴力梦颁布为特征。我们最近报告说RBD增加了 与没有神经特征的退伍军人相比，与合并症TBI+PTSD的退伍军人相比，超过两倍。这 在RBD患者中看到的无atonia（RSWA）的异常REM睡眠被广泛认为是 最早的突触核苷临床表现，因为50-70％的RBD患者最终phenoconvert 帕金森氏病（PD）或相关疾病。来自几项流行病学研究的新兴证据， 包括我们自己的包括我们自己的，都建议TBI和PTSD协同作用，以增加以后发展的风险 PD。但是，我们理解的主要差距仍然存在。我们仍然需要更好地了解预测因子和 神经疾病导致易感人群中RBD和突触核苷的神经途径，以及 我们需要确定候选疗法和窗户，以进行潜在的神经保护干预措施 防止表现。这些差距将在3个目标中解决。 AIM 1将决定行为 使用组合TBI+PTSD的小鼠模型的RSWA相关。使用我们先前建立的模型 TBI+PTSD结合，小鼠将受到控制的皮质影响和单一的延长应力程序， 随后进行步态分析，恐惧调节和睡眠脑电图（EEG）/肌电图 （EMG）量化RSWA的录音。然后，在创伤的基础上将小鼠隔离为3组 暴露和行为严重程度：神经特征（NT），外伤暴露（行为正常）和 控件（未暴露于创伤）。在AIM 1中，我们假设NT组中的小鼠将显示出增加 与TE和对照相比，RSWA的严重性将预测 NT组中的RSWA。在AIM 2中，我们将确定RSWA和 行为通过使用创新的新方法在用TBI+PTSD的小鼠中定义小鼠，以对大脑血流进行图像 具有功能性超声（FUS）的活动物。我们假设NT组中的小鼠将显示 杏仁核内部功能连通性的提高将与行为和行为的读数相关 RSWA。在AIM 3中，我们将确定神经头如何对RSWA和突触核蛋白动态贡献 SynGFP转基因小鼠，并测试姜黄素减慢此过程的能力。我们将使用A53T SyngFP 小鼠，一种已建立的小鼠模型的加速突触核疾病模型，密切模仿人类状况， 结合我们的TBI+PTSD和睡眠记录的方法。我们假设Neurotrauma将 加速α-核蛋白沉积，姜黄素会减少α-核蛋白燃烧并改善 行为定义了新约小鼠。这些研究的结果将提供有价值的机械信息 关于神经术对REM睡眠和突触核酸的影响的病理生理学以及 测试潜在的承诺治疗干预措施。有了这些批判知识，我们将采取重要步骤 通过TBI/PTSD更好地预测和减轻退伍军人的潜在神经退行性。