Mechanisms of Cortico-Limbic Network Dysfunction Underlying PTSD after TBI

 说明： 创伤性脑损伤(TBI)被认为是美国最近战时冲突中的“标志性”损伤，大约15%的作战人员经历了单次或多次轻度脑损伤(MTBI)。创伤后应激障碍在这一人群中是一种常见的共病，几乎35%暴露于mTBI的退伍军人报告了与他们在战区服役有关的合格症状。对于轻度创伤性脑损伤(MTBI)是否导致创伤后应激障碍(PTSD)的易感性，或者mTBI是否在机制上导致了PTSD症状的某些方面，仍然存在很大的争议。在mTBI和PTSD的症状学上有很大的重叠，这表明要么是大量的mTBI暴露也是心理创伤，要么是单个或多个MTBI后存在潜在的生物学底物，使退伍军人容易患上PTSD或其相关症状。创伤后应激障碍的症状表现(即情绪调节障碍和认知障碍)可能是脑创伤后情绪处理和记忆的大脑区域协调的生物力学破坏的潜在基础。这种同样的干扰可能会干扰有效的治疗，特别是包括灭绝范式的长期暴露(PE)。为了揭示脑外伤对创伤后应激障碍的脑回路的影响，动物模型是必要的。因此，我们将利用生物力学上最真实的弥漫性脑损伤模型，猪旋转加速模型，来阐明mTBI是如何影响脑损伤的。 创伤后应激障碍背后的电路和创伤后应激障碍样行为表型的获得和消亡。我们将利用恐惧条件作用在猪身上产生类似创伤后应激障碍的表型。边缘系统是一组涉及认知、记忆和情绪突显处理的大脑区域，通过这些网络之间的振荡活动高度联系在一起。 我们的中心假设是弥漫性脑损伤导致皮质边缘系统内部和区域之间的破坏，增加杏仁核对其他边缘结构的优势，从而导致对创伤后应激障碍样表型的易感性和灭绝失败。脑损伤还可能扰乱消除创伤后症状所需的回路，并对重新巩固记忆所涉及的睡眠模式产生不利影响。我们将通过检测单次和重复旋转加速损伤后皮质-边缘系统的神经生理学变化和相关行为，包括睡眠-觉醒结构，来研究与创伤相关的创伤后应激障碍症状和治疗耐药性的机制。为了达到这些目的，猪将在诱发mTBI的加速度水平上重复(2倍)损伤，然后在损伤后的多个时间点进行实验。可广泛覆盖皮质-边缘回路的多个电极阵列将在麻醉下植入，并在依赖皮质-边缘回路的行为任务期间，在损伤后3-4周内进行监测。另一组动物将是创伤后恐惧条件反射，以检测创伤后恐惧获得(即，创伤后应激障碍样表型的发展)的变化。另一组动物将在受伤前接受恐惧条件处理，这样就可以检查随后受伤(与假伤害相比)对消除恐惧的影响。由于睡眠障碍是创伤后应激障碍和脑外伤的显著重叠症状，所有动物，无论是受伤的还是假受伤的，都将被监测睡眠-觉醒结构的变化。快速眼动(REM)S EEP宏观和微观结构将被检查，因为有大量证据表明快速眼动睡眠异常在创伤后应激障碍。在所有实验中，睡眠测量将与电生理测量相关联。然后，动物将被处死，电生理发现与海马体、前额叶皮质、杏仁体及其连接轴突的组织病理学分析相关联。因此，这项拟议的研究将通过检测猪弥漫性脑损伤模型中相关皮质-边缘网络的神经生理学变化来评估脑外伤和创伤后应激障碍并发的机制(S)。

 DESCRIPTION: Traumatic Brain Injury (TBI) is considered the "signature" injury of the recent US wartime conflicts, with approximately 15% of warfighters experiencing single or multiple mild TBIs (mTBI). PTSD is a frequent comorbidity in this population, with almost 35% of mTBI exposed Veterans reporting qualifying symptoms associated with their service in theater. A great deal of controversy remains over whether mild traumatic brain injury (mTBI) contributes to the susceptibility for post-traumatic stress disorder (PTSD), or whether mTBI mechanistically underlies some aspects of presenting PTSD symptoms. There is a great deal of overlap in the symptomatology of mTBI and PTSD, suggesting that either a large subpopulation of mTBI exposures are also psychologically traumatic, or that there is an underlying biological substrate after single or multiple mTBIs that predisposes Veterans to PTSD or its associated symptoms. The presenting symptomatology of PTSD (i.e., emotion dysregulation and cognitive deficits) may have an underlying basis in the biomechanical disruption by TBI of the coordination of brain areas for emotional processing and memory. This same disruption may interfere with effective treatment, in particular prolonged exposure (PE), which incorporates an extinction paradigm. Animal models are necessary in order to unravel the effect of TBI on the brain circuitry underlying PTSD. We will therefore utilize the most biomechanically realistic model of diffuse brain injury, the porcine rotational acceleration model, in order to elucidate how mTBI affects the circuitry underlying PTSD and the acquisition and extinction of PTSD-like behavioral phenotypes. We will utilize fear conditioning in order to produce a PTSD-like phenotype in swine. The limbic system, a group of brain regions involved in cognition, memory and processing of emotional salience, is highly linked via oscillatory activity between these networks. Our central hypothesis is that diffuse TBI leads to a disruption within and between areas of the corticolimbic system, increasing dominance of the amygdala over other limbic structures and thus leading to a susceptibility to PTSD-like phenotypes and failure of extinction. TBI may also disrupt the very circuitry required to extinguish post-traumatic symptoms, and adversely affect sleep patterns involved in reconsolidation of memory. We will investigate the mechanisms underlying TBI- related PTSD symptoms and treatment resistance by examining neurophysiological changes in the cortico-limbic system and related behaviors, including sleep-wake architecture, after single and repetitive rotational acceleration injury. To accomplish these aims, swine will be injured repetitively (2x) at acceleration levels inducing mTBI, and then experiments will proceed at multiple time-points post-injury. Multiple electrode arrays that allow for extensive coverage of the cortico-limbic circuit will be implanted under anesthesia and monitored over a period of 3-4 weeks post-injury, during behavioral tasks dependent on cortico-limbic circuitry. Another group of animals will be fear conditioned post-injury in order to detect changes in fear acquisition (i.e., the development of a PTSD-like phenotype) post-TBI. Another group of animals will be fear-conditioned prior to injury so that the effect of subsequent injury (compared to sham injury) on the extinction of fear can be examined. As sleep disruption is a prominent overlapping symptom of PTSD and TBI, all animals, injured and sham injured will be monitored for changes in sleep-wake architecture. Rapid eye movement (REM) s eep macro- and microarchitecture will be examined as there is substantial evidence for REM sleep abnormalities in PTSD. In all experiments, sleep measures will be correlated with electrophysiological measures. The animals will then be sacrificed, and the electrophysiological findings correlated with histopathological analysis of the hippocampus, prefrontal cortex, and amygdala and their connecting axonal tracts. The proposed studies will therefore assess the mechanism(s) underlying comorbid TBI and PTSD by examining the neurophysiological changes in the relevant cortico-limbic networks in a porcine model of diffuse brain injury.