Role of dentate gyrus gating and neurogenesis in the pathophysiology of mild TBI

描述(申请人提供)：创伤性脑损伤(TBI)每年在美国影响大约170万人，据估计高达75%的此类损伤 被归类为轻度脑外伤。然而，用“轻度”一词来描述是不够的，因为轻度脑外伤(MTBI)通常伴随着严重的认知缺陷，通常表现为 学习和记忆、注意力和情绪控制方面的长期变化。尽管轻度脑外伤发生率高且往往影响持久，但导致长期认知缺陷的因素仍不清楚。因此，该项目的目标是确定可能导致mTBI导致的长期缺陷的神经元功能变化。根据我们的初步数据，我们假设mTBI导致齿状回的结构和功能改变，从而导致持久的认知障碍。齿状回的一个主要功能是限制神经活动通过海马体的流动。这个“门控”功能是 对于将稀疏的皮质感觉信号传播到下游锥体细胞是必不可少的，是通过强大的局部抑制电路实现的。此外，齿状回是神经前体细胞不断产生新生神经元的两个大脑区域之一。我们的初步数据表明，mTBI的一次发作严重破坏了抑制和兴奋的平衡，紧随其后的是持续数月的神经发生的强劲增强。我们认为，齿状门的短暂破坏导致了活动诱导的神经发生的增强，并预测mTBI诱导的神经发生对齿状回功能具有长期的有害影响，从而导致激光认知障碍。使用临床相关的mTBI小鼠模型，我们将使用三个特定的目标来评估我们的假设。首先，我们将在海马片上利用电生理学技术确定mTBI如何改变齿状回的门控功能，并在mTBI后的活体实验中证实这些发现。在第二个目标中，我们将使用转基因报告鼠来确定mTBI如何改变mTBI诱导的新神经元的结构和功能特性。我们将评估新产生的细胞如何整合到齿状回的回路中，并影响门控功能。在第三个目标中，我们将测试齿状改变有助于认知障碍的假设。在出现齿状异常的时间点，接受mTBI的小鼠将在各种成熟的行为范式中进行评估，以测试学习、记忆、注意力和情绪控制。我们还将测试操纵门控和神经再生是否足以概括和阻止mTBI造成的行为损害。该项目的成功完成将阐明mTBI后认知障碍的潜在机制，并确定治疗最常见形式的脑损伤的新靶点。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects approximately 1.7 million people in the United States every year and it is estimated that up to 75% of these injuries are classified as mild TBI. However, the word "mild" is an inadequate description as mild TBI (mTBI) is typically accompanied acutely by significant deficits in cognition that often manifest as long-term alterations in learning and memory, attention, and emotional control. Despite the high incidence and often lasting impact of mild TBI, the factors that induce long-term cognitive deficits remain unknown. Consequently, the goal of this project is to identify alterations in neuronal function that may underlie long-term deficits caused by mTBI. Based on our preliminary data, we hypothesize that mTBI causes structural and functional alterations in the dentate gyrus that contribute to lasting cognitive deficits. A principal function of the dentate gyrus is to restrict the flow of neural activity through the hippocampus. This "gating" function is essential for propagating sparse representation of cortical sensory signals to downstream pyramidal cells and is achieved by strong local inhibitory circuitry. Furthermore, the dentate gyrus is one of two brain regions where neural progenitor cells continuously generate newborn neurons. Our preliminary data indicate that a single episode of mTBI acutely disrupts the balance of inhibition and excitation and is followed by a robust enhancement in neurogenesis that persists for months. We propose that the transient breakdown of the dentate gate leads to activity-induced enhanced neurogenesis and predict that mTBI-induced neurogenesis has long-term detrimental effects on dentate function that contribute to lasing cognitive impairments. Using a clinically-relevant mouse model of mTBI, we will evaluate our hypothesis using three specific aims. First, we will determine how mTBI alters the gating function of the dentate gyrus using electrophysiological techniques in hippocampal slices and corroborate these findings in vivo after mTBI. In the second aim, we will use transgenic reporter mice to determine how mTBI alters the structural and functional properties of mTBI-induced new neurons. We will evaluate how newly generated cells integrate into the circuitry of the dentate gyrus and affect the gating function. In the third aim, we will test the hypothesis that dentate alterations contribute to cognitive impairments. At time points when dentate abnormalities are present, mice that received mTBI will be evaluated in a variety of well-established behavioral paradigms to test learning, memory, attention and emotional control. We will also test whether manipulating gating and neurogenesis are sufficient to recapitulate and block the behavioral impairments caused by mTBI. The successful completion of this project will elucidate a potential mechanism for cognitive deficits after mTBI as well as identify novel targets for treating the most common form of brain injury.