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 在从军事部署返回的美国退伍军人中普遍存在，大约增加了 10-20% 最近中东的冲突除了许多令人丧失能力的白天症状外，我们和其他人还遇到了这种情况。 研究表明，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 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作用。 睡眠期间肌张力下降 在快速眼动 (REM) 睡眠期间，骨骼广泛麻痹。 肌肉通常会发生——这是一个在快速眼动睡眠行为障碍 (RBD) 中失调的过程， 其特点是快速眼动睡眠期间的剧烈梦境表现，我们最近报道 RBD 增加。 与没有神经外伤的退伍军人相比，患有 TBI+PTSD 共病的退伍军人的两倍以上。 RBD 患者中出现的异常 REM 睡眠无 Atonia (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 患者最终会出现表型转变 多项流行病学研究的新证据， 包括我们自己的研究人员都认为，TBI 和 PTSD 会协同作用，从而增加以后发生抑郁症的风险。 然而，我们的理解仍然存在重大差距，需要更好地理解预测因素和预测因素。 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措施的窗口，以便 防止表型转化。目标 1 将确定行为，从而解决这些差距。 使用我们之前建立的 TBI+PTSD 小鼠模型来关联 RSWA。 结合 TBI+PTSD，小鼠将经历受控的皮质冲击和单次长时间的应激程序， 随后进行步态分析、恐惧调节和睡眠脑电图 (EEG)/肌电图 (EMG) 记录以量化 RSWA，然后根据创伤将小鼠分为 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（未遭受创伤）在目标 1 中，我们认为 NT 组的小鼠会表现出增加。 RSWA 与 TE 和对照相比，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 和基础的大脑功能连接。 通过使用创新的新方法对脑血流进行成像，研究患有 TBI+PTSD 的小鼠的行为缺陷 我们追踪到 NT 组的小鼠将表现出功能性超快超声 (fUS)。 杏仁核内的功能连接增加，这将与行为和行为的读数相关联 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 A53T SynGFP。 小鼠，一种已建立的加速突触核蛋白病小鼠模型，与人类状况非常相似， 结合我们的 TBI+PTSD 方法和睡眠记录，我们发现神经创伤会发生。 加速 α-突触核蛋白沉积，姜黄素会减少 α-突触核蛋白负担并改善 NT 小鼠的行为缺陷将提供有价值的机制信息。 关于神经创伤对快速眼动睡眠和突触核蛋白病影响的病理生理学，以及 有了这些关键的知识，我们将采取重要的步骤来测试潜在的治疗干预措施。 在更好地预测和减轻患有 TBI/PTSD 的退伍军人中潜在的神经退行性疾病方面取得了进展。