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

描述（由申请人提供）：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% 被归类为轻度创伤性脑损伤然而，“轻度”一词是不充分的描述，因为轻度TBI（mTBI）通常急性地伴随着显著的认知缺陷，其通常表现为 学习和记忆，注意力和情绪控制的长期改变。尽管轻度TBI的发病率很高，而且往往具有持久的影响，但导致长期认知缺陷的因素仍然未知。因此，该项目的目标是确定可能导致mTBI引起的长期缺陷的神经元功能的改变。基于我们的初步数据，我们假设mTBI导致齿状回的结构和功能改变，导致持久的认知缺陷。齿状回的主要功能是限制神经活动通过海马体的流动。这种“门控”功能是 对于将皮质感觉信号的稀疏表示传播到下游锥体细胞是必需的，并且通过强的局部抑制回路来实现。此外，齿状回是神经祖细胞持续产生新生神经元的两个脑区之一。我们的初步数据表明，单次mTBI急性破坏了抑制和兴奋的平衡，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具有长期的不利影响，从而导致激光认知障碍。使用mTBI的临床相关小鼠模型，我们将使用三个特定目标评估我们的假设。首先，我们将确定如何mTBI改变门控功能的齿状回使用电生理技术在海马切片和证实这些发现在体内mTBI后。在第二个目标中，我们将使用转基因报告小鼠来确定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电路中并影响门控功能。在第三个目标中，我们将测试的假设，齿状改变有助于认知障碍。在存在齿状异常的时间点，接受mTBI的小鼠将在各种完善的行为范例中进行评估，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发生是否足以概括和阻断由mTBI引起的行为障碍。该项目的成功完成将阐明mTBI后认知缺陷的潜在机制，并确定治疗最常见形式的脑损伤的新靶点。 公共卫生相关性：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，“轻度”一词是不充分的描述，因为轻度TBI（mTBI）通常伴随着严重的认知缺陷，其通常表现为学习和记忆、注意力和情绪控制的长期改变。本文提出的研究将阐明mTBI后认知缺陷的潜在机制，并确定治疗这种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. PUBLIC HEALTH RELEVANCE: 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. The research proposed here will elucidate a potential mechanism for cognitive deficits after mTBI as well as identify novel targets for treating this most common form of brain injury.