Effects of traumatic brain injury on temporal dynamics of brain activity and learning

 描述(由申请人提供)：轻度创伤性脑损伤(TBI)可导致情感和认知障碍，在创伤事件发生后持续数月至数年。这些缺陷主要包括抑郁和无法消除恐惧记忆(导致恐惧持续)，这是《精神疾病诊断和统计手册-IV》(DSM-IV)定义的震荡后综合症(PCS)的一部分。轻微的创伤性脑损伤通常是由主爆震波后闭合头部的侮辱、头部的打击或碰撞过程中头部的加减速造成的。它在军事战斗、体育运动、娱乐活动和车辆事故中非常频繁地发生，因此构成了一个重大的公共心理健康问题。轻度颅脑损伤后观察到的主要脑病理是弥漫性轴索损伤，尽管也怀疑持续性神经元功能障碍。轻微的脑外伤会破坏其连接和功能，从而导致神经精神障碍，其确切的大脑区域一直不确定。基于我们的初步发现，我们建议使用轻度脑损伤的小鼠模型来研究内侧前额叶皮质(MPFC)的电生理异常在恐惧持续和抑郁的发生中的作用，这是轻度脑损伤的两种更具致残性的神经精神后遗症，目前还没有治疗方法。我们还将证实，我们已经证明的一种新药，可以减少小鼠轻度脑外伤后的抑郁和恐惧，这是通过正常化mPFC一致性来实现的。我们建议的研究是基于我们的初步发现，使用多点记录的轻微脑损伤小鼠的神经元活动，引起 通过精确控制的超压空气冲击波限制在左侧前脑上方的头盖骨。我们的结果表明，内侧前额叶皮质(MPFC)神经元放电的异常相干性在经历轻度脑损伤后一年内表现出持久抑郁和无法消除恐惧记忆的小鼠中持续存在。相比之下，经历了亚震荡空气冲击波或假空气冲击波的小鼠显示出mPFC神经元放电的正常一致性，此后没有抑郁或持续性恐惧。此外，用新型药物(大麻素2型受体反向激动剂SMM-189)治疗小鼠，不仅在mTBI后1个月改善了恐惧和抑郁，还将mPFC的连贯性恢复到正常值。因此，我们的初步发现的确认可能会促进我们对轻度脑外伤后持续抑郁和恐惧背后的神经机制的理解，并可能提供一个电生理信号，可以用来识别哪些人的持续抑郁和恐惧很可能是由mTBI引起的。因此，我们建议检验这一假设，即mPFC中神经元振荡的一致性与轻度脑损伤后持续的抑郁和恐惧密切相关，并因此成为其原因。我们还建议验证这样一种假设，即SMM-189通过恢复mPFC中正常的神经元连贯性来拯救mTBI相关的恐惧和抑郁缺陷，并且进一步研究SMM-189可能因此导致一种可能的药物治疗mTBI。

 DESCRIPTION (provided by applicant): Mild traumatic brain injury (TBI) can cause emotional and cognitive deficits that last for months to years after the traumatic event. These deficits prominently include depression and an inability to extinguish fearful memories (leading to fear perseveration), which are part of the Post Concussion Syndrome (PCS) as defined in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). Mild TBI typically results from a closed-head insult after a primary blast shock wave, a blow to the head, or head acceleration - deceleration during a collision. It is an extremely frequent occurrence during military combat, sports, recreational activities, and vehicular accidents and thus constitutes a significant public mental health problem. The major brain pathology observed after mild TBI is diffuse axonal injury, although persistent neuronal dysfunction is suspected as well. The precise brain regions whose connectivity and function are disrupted by mild TBI so as to cause neuropsychiatric deficits have been uncertain. Based on our initial findings, we propose to use a mouse model of mild TBI to study the role of electrophysiological abnormalities in medial prefrontal cortex (mPFC) in the genesis of fear perseveration and depression, two of the more disabling neuropsychiatric sequela of mild TBI, for which there is currently no treatment. We will also confirm that a novel drug that we have shown to reduce depression and fear after mild TBI in mice, does so by normalizing mPFC coherence. Our proposed studies are based on our preliminary findings using multi-site recordings of neuronal activity in mice with mild TBI, caused by a precisely controlled overpressure air blast restricted to the cranium overlying the left forebrain. Our results suggest that abnormal phase coherence of neuronal firing in the medial prefrontal cortex (mPFC) is persistently present in mice that show enduring depression and an inability to extinguish fear memories up to one year after they experienced mild TBI. By contrast, mice that had experienced a subconcussive air blast or a sham air blast showed normal coherence of neuronal firing in mPFC and no depression or perseverative fear afterwards. Furthermore, treating mice with the novel drug (the cannabinoid type-2 receptor inverse agonist SMM-189) not only ameliorated fear and depression at 1 month after mTBI, it also restored coherence in the mPFC to normal values. Confirmation of our preliminary findings is thus likely to advance our understanding of the neuronal mechanisms behind persistent depression and fear after mild TBI, and may provide an electrophysiological signature that can be used to identify those humans whose persistent depression and fear is likely to arise from mTBI. We therefore propose to test the hypothesis that coherence of neuronal oscillations in mPFC is tightly associated with and thus causal to the persistent depression and fear after mild TBI. We also propose to test the hypothesis that SMM-189 rescues mTBI related fear and depression deficits in mice by restoring normal neuronal coherence in the mPFC, and that further investigation of SMM-189 may thus lead to a possible pharmacological treatment for mTBI.