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

点击翻译按钮获取中文摘要

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.