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

摘要/摘要变更受资助机构申请 创伤性脑损伤（TBI）每年影响美国约170万人， 据估计，这些损伤中高达75%被归类为轻度TBI。然而，“温和”这个词是一个 轻度TBI（mTBI）的描述不充分，通常伴有严重的认知缺陷 这通常表现为学习和记忆，注意力和情绪控制的长期变化。尽管 轻度TBI的高发病率和通常持久的影响，诱发长期认知缺陷的因素 仍然未知。因此，本项目的目标是确定神经元功能的改变， 这是mTBI造成的长期赤字的基础。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，有助于持久的认知 赤字齿状回的主要功能是限制神经活动通过齿状回的流动。 海马体。这种“门控”功能对于传播皮层感觉的稀疏表示是必不可少的。 向下游锥体细胞发出信号，并通过强的局部抑制回路实现。而且 齿状回是神经前体细胞持续产生新生儿的两个脑区之一， 神经元我们的初步数据表明，单次mTBI急性破坏了抑制的平衡， 和兴奋，随后是持续数月的神经发生的强烈增强。我们提出 齿状门的瞬时击穿导致活动诱导的增强的神经发生，并预测 mTBI诱导的神经发生对齿状功能有长期的有害影响， 认知障碍使用临床相关的mTBI小鼠模型，我们将使用以下方法评估我们的假设： 三个具体目标。首先，我们将确定mTBI如何改变齿状回的门控功能， 在海马切片的电生理技术，并证实这些发现在体内后mTBI。在 第二个目标，我们将使用转基因报告小鼠，以确定如何mTBI改变结构和功能， mTBI诱导的新神经元的性质。我们将评估新生成的细胞如何整合到 齿状回的电路并影响门控功能。在第三个目标中，我们将检验以下假设： 牙齿的改变会导致认知障碍在出现齿状异常的时间点， 接受mTBI的小鼠将在各种良好建立的行为范例中进行评价以测试学习， 记忆力注意力和情绪控制我们还将测试是否操纵门控和神经发生， 足以概括和阻断由mTBI引起的行为障碍。圆满完成 该项目将阐明mTBI后认知缺陷的潜在机制，并确定新的 治疗最常见的脑损伤的靶点。

Summary/ Abstract CHANGE OF GRANTEE ORGANIZATION REQUEST 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.