Mechanisms of Cortico-Limbic Network Dysfunction Underlying PTSD after TBI

 产品说明： 创伤性脑损伤（TBI）被认为是最近美国战时冲突的“标志性”损伤，大约15%的战士经历了单一或多个轻度TBI（mTBI）。PTSD是这一人群中常见的并发症，几乎35%的mTBI暴露退伍军人报告与他们在剧院服务相关的合格症状。关于轻度创伤性脑损伤（mTBI）是否有助于创伤后应激障碍（PTSD）的易感性，或者mTBI是否在机械上构成了PTSD症状的某些方面，仍然存在很大的争议。在mTBI和PTSD的发病学中有大量的重叠，这表明mTBI暴露的大亚群也是心理创伤，或者在单次或多次mTBI后存在潜在的生物基质，使退伍军人易患PTSD或其相关症状。PTSD的表现形式（即，情绪调节障碍和认知缺陷）可能具有由TBI对用于情绪处理和记忆的脑区域的协调的生物力学破坏的潜在基础。同样的破坏可能会干扰有效的治疗，特别是长期暴露（PE），其中包括灭绝范式。为了揭示创伤性脑损伤对PTSD脑回路的影响，动物模型是必要的。因此，我们将利用弥漫性脑损伤的最生物力学现实的模型，猪旋转加速度模型，以阐明mTBI如何影响脑损伤。 PTSD和PTSD样行为表型的获得和消失的潜在电路。我们将利用恐惧条件反射在猪中产生PTSD样表型。边缘系统是一组参与认知、记忆和情绪显著性处理的大脑区域，通过这些网络之间的振荡活动高度联系。 我们的中心假设是，弥漫性TBI导致皮质边缘系统的区域内和区域之间的中断，增加杏仁核对其他边缘结构的优势，从而导致对PTSD样表型的易感性和灭绝的失败。创伤性脑损伤还可能破坏消除创伤后症状所需的电路，并对记忆再巩固所涉及的睡眠模式产生不利影响。我们将通过检查皮质边缘系统和相关行为的神经生理学变化，包括单次和重复旋转加速度损伤后的睡眠-觉醒结构，研究TBI相关PTSD症状和治疗抵抗的潜在机制。为了实现这些目标，猪将在诱导mTBI的加速度水平下重复受伤（2x），然后实验将在受伤后的多个时间点进行。将在麻醉下植入允许广泛覆盖皮质边缘回路的多个电极阵列，并在损伤后3-4周的时间内，在依赖于皮质边缘回路的行为任务期间进行监测。另一组动物将在损伤后进行恐惧条件化以检测恐惧获得的变化（即，PTSD样表型的发展）。另一组动物将在受伤前进行恐惧调节，以便检查随后的损伤（与假损伤相比）对恐惧消退的影响。由于睡眠中断是PTSD和TBI的突出重叠症状，因此将监测所有动物（受伤和假受伤）的睡眠-觉醒结构变化。快速眼动（REM）睡眠的宏观和微观结构将进行检查，因为有大量的证据表明，快速眼动睡眠异常的创伤后应激障碍。在所有实验中，睡眠测量将与电生理测量相关。然后处死动物，并将电生理学结果与海马、前额叶皮质和杏仁核及其连接轴突束的组织病理学分析相关联。因此，拟议的研究将通过检查弥漫性脑损伤猪模型中相关皮质边缘网络的神经生理学变化来评估TBI和PTSD共病的潜在机制。

 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.