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）可导致情感和认知缺陷，在创伤事件后持续数月至数年。这些缺陷主要包括抑郁症和无法消除恐惧记忆（导致恐惧持续），这是精神障碍诊断和统计手册-IV（DSM-IV）中定义的脑震荡后综合征（PCS）的一部分。轻度TBI通常是由主爆炸冲击波、头部撞击或碰撞期间头部加速-减速后的闭合头部损伤引起的。它在军事战斗、体育、娱乐活动和交通事故中极为频繁，因此构成了一个重大的公共心理健康问题。轻度TBI后观察到的主要脑病理学是弥漫性轴索损伤，尽管也怀疑持续的神经元功能障碍。轻度TBI导致神经精神缺陷的确切脑区的连接和功能被破坏，这一点尚不确定。基于我们的初步研究结果，我们建议使用小鼠模型轻度TBI的内侧前额叶皮层（mPFC）的电生理异常的恐惧持续和抑郁症，两个更残疾的轻度TBI的神经精神后遗症，目前没有治疗的起源研究的作用。我们还将证实，我们已经证明可以减轻小鼠轻度TBI后抑郁和恐惧的一种新药，通过使mPFC连贯性正常化来实现这一点。我们提出的研究是基于我们的初步发现，使用多位点记录轻度TBI小鼠的神经元活动， 通过一个精确控制的超压空气爆炸限制在头盖骨覆盖左前脑。我们的研究结果表明，异常相位一致性的神经元放电在内侧前额叶皮层（mPFC）是持续存在的小鼠表现出持久的抑郁症和无法消除恐惧记忆长达一年后，他们经历了轻度TBI。相比之下，经历了亚震荡空气冲击或假空气冲击的小鼠显示出mPFC中神经元放电的正常一致性，并且之后没有抑郁或持续恐惧。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，我们的初步研究结果的确认可能会促进我们对轻度TBI后持续抑郁和恐惧背后的神经元机制的理解，并可能提供一个电生理特征，可用于识别那些持续抑郁和恐惧的人可能是由mTBI引起的。因此，我们建议测试的假设，即一致性的mPFC神经元振荡是密切相关的，从而导致持续的抑郁和恐惧后，轻度TBI。我们还建议测试的假设，即SMM-189救援mTBI相关的恐惧和抑郁症的缺陷，小鼠通过恢复正常的神经元的连贯性mPFC，SMM-189的进一步调查，因此可能导致一个可能的药理治疗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.