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

齿状回门控和神经发生在轻度 TBI 病理生理学中的作用

• 批准号: 8481602
• 负责人: CANDACE L. FLOYD
• 金额: $ 30.54万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8481602
• 关键词: Acute; Address; Adult; Affect; Anxiety; Attention; Behavior; Behavioral; Behavioral Paradigm; Brain Injuries; Brain region; Cells; Cognition; Cognitive; Cognitive deficits; Data; Development; Emotional; Equilibrium; Functional disorder; Goals; Hippocampus (Brain); Impaired cognition; In Vitro; Incidence; Injury; Interneurons; Learning; MRI Scans; Memory; Morphology; Mus; Neurons; Newborn Infant; Patients; Pattern; Performance; Persons; Property; Pyramidal Cells; Relative (related person); Reporter; Reporting; Research; Role; Sensory; Signal Transduction; Slice; Staging; Synapses; Tamoxifen; Techniques; Testing; Time; Transgenic Organisms; Traumatic Brain Injury; United States; Whole-Cell Recordings; X-Ray Computed Tomography; base; behavioral impairment; clinically relevant; dentate gyrus; disability; in vivo; insight; mouse model; nerve stem cell; neurobehavioral; neurogenesis; newborn neuron; novel; relating to nervous system; research study; synaptic inhibition

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.

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，估计其中高达 75% 被归类为轻度 TBI。然而，“轻度”一词的描述并不充分，因为轻度 TBI (mTBI) 通常严重伴有严重的认知缺陷，通常表现为 学习和记忆、注意力和情绪控制的长期改变。尽管轻度创伤性脑损伤的发生率很高且影响往往持久，但引起长期认知缺陷的因素仍然未知。因此，该项目的目标是确定神经元功能的改变，这些改变可能是 mTBI 引起的长期缺陷的基础。根据我们的初步数据，我们假设 mTBI 会导致齿状回的结构和功能改变，从而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。这个“门控”功能是 这对于将皮质感觉信号的稀疏表示传播到下游锥体细胞至关重要，并且是通过强大的局部抑制电路来实现的。此外，齿状回是神经祖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，单次 mTBI 会严重破坏抑制和兴奋的平衡，随后神经发生会持续数月的强劲增强。我们提出，齿状门的短暂崩溃会导致活动诱导的神经发生增强，并预测 mTBI 诱导的神经发生会对齿状功能产生长期有害影响，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目标来评估我们的假设。首先，我们将使用海马切片中的电生理技术确定 mTBI 如何改变齿状回的门控功能，并在 mTBI 后在体内证实这些发现。第二个目标是，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。我们将评估新生成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，我们将检验齿状改变导致认知障碍的假设。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发生是否足以重现和阻止 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。