Normal and Pathological Function of the Dentate Gyrus

齿状回的正常和病理功能

• 批准号: 8460341
• 负责人: DOUGLAS A COULTER
• 金额: $ 36.64万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460341
• 关键词: Action Potentials; Adult; Animal Model; Animals; Area; Behavior; Birth; Brain; Calcium; Cells; Code; Cognitive; Cognitive deficits; Comorbidity; Control Animal; Decision Making; Development; Dyes; Emotions; Environment; Epilepsy; Episodic memory; Exhibits; Feedback; Frequencies; Gene Targeting; Generations; Hippocampus (Brain); Image; Imaging Techniques; In Vitro; Individual; Interneurons; Learning; Limbic System; Mediating; Memory; Moods; Nature; Neurons; Patients; Pattern; Play; Population; Probability; Process; Property; Regulation; Relative (related person); Reporter; Role; Seizures; Series; Shapes; Specificity; Stochastic Processes; Structure; Techniques; Testing; Time; Transgenic Organisms; cognitive function; dentate gyrus; effective therapy; entorhinal cortex; experience; granule cell; in vivo; insight; memory process; nerve supply; optogenetics; patch clamp; response; therapy development; voltage

DESCRIPTION (provided by applicant): The dentate gyrus is a critical contributor in the cognitive functions of the hippocampus. The principal cells of the dentate gyrus, dentate granule cells, exhibit firing in small subpopulations during execution of cognitive tasks, consistent with the process of sparse coding. Sparse coding is a stochastic process. This may not apply to the dentate gyrus, since small populations of cells exhibit preferential activation in multiple environments, while others remain persistently silent, a deterministic firing pattern. The mechanisms responsible for this are entirely unknown, but the birth of new granule cells in the adult brain may contribute. The dentate gyrus also regulates pathological activation of the limbic system. This function, when compromised, may contribute to epilepsy development. In patients with epilepsy, in addition to seizures, there are cognitive deficits that arise associated with damage to the dentate gyrus and other hippocampal structures. In this proposal, we will utilize advanced imaging, patch clamp, optogenetic, and transgenic techniques to test the hypothesis that sparse, deterministic firing of granule cells emerges as a specific consequence of tailored inhibitory function within the dentate gyrus, and this exhibits significant erosion in animals with epilepsy. We propose to characterize network firing in the dentate gyrus, determine the contributions of adult born granule cells to these firing properties, and examine dentate network activation in animals with epilepsy. Little is known about the mechanisms mediating cellular activation in the dentate gyrus, and how epilepsy development may erode these processes. In addition to seizures, patients with epilepsy exhibit severe cognitive co-morbidities, including deficits in emotion, mood, and learning and memory, typically thought of as limbic system functions. Understanding how epilepsy development alters limbic circuit properties is important both in targeting new therapies for seizure amelioration, and in developing treatments to reduce co-morbid conditions associated with seizure disorders. PUBLIC HEALTH RELEVANCE: Despite the fact that the dentate gyrus is a critical regulator of the cognitive functions of the hippocampus, we know little about the mechanisms determining its activation properties, either in normal, healthy individuals or in patients with epilepsy. This proposal will examine these mechanisms using advanced imaging, patch clamp recording, gene targeting, and optogenetic techniques, focusing on how individual neurons within the dentate gyrus make the decision to activate or remain silent, both in normal animals, and in animal models of epilepsy. Insight derived from these studies should facilitate the development of better, more effective treatments for both epilepsy, and associated co-morbidities accompanying epilepsy development.

描述（由申请人提供）：齿状回是海马体认知功能的关键贡献者。齿状回的主要细胞，即齿状颗粒细胞，在执行认知任务期间表现出小亚群的放电，这与稀疏编码的过程一致。稀疏编码是一个随机过程。这可能不适用于齿状回，因为少数细胞在多种环境中表现出优先激活，而其他细胞则保持持续沉默，这是一种确定性的放电模式。造成这种现象的机制完全未知，但成人大脑中新颗粒细胞的诞生可能有所贡献。齿状回还调节边缘系统的病理激活。当这种功能受到损害时，可能会导致癫痫的发展。在癫痫患者中，除了癫痫发作之外，还存在与齿状回和其他海马结构损伤相关的认知缺陷。在本提案中，我们将利用先进的成像、膜片钳、光遗传学和转基因技术来检验以下假设：颗粒细胞的稀疏、确定性放电是齿状回内定制抑制功能的特定结果，并且这在齿状回中表现出显着的侵蚀。动物与 癫痫。我们建议描述齿状回网络放电的特征，确定成年颗粒细胞对这些放电特性的贡献，并检查癫痫动物的齿状网络激活。人们对介导齿状回细胞激活的机制以及癫痫的发展如何破坏这些过程知之甚少。除了癫痫发作之外，癫痫患者还表现出严重的认知共病，包括情绪、情绪、学习和记忆缺陷，通常被认为是边缘系统功能缺陷。了解癫痫的发展如何改变边缘回路特性对于寻找改善癫痫发作的新疗法以及开发减少与癫痫症相关的共病的治疗方法都很重要。 公共健康相关性：尽管齿状回是海马体认知功能的关键调节因子，但我们对决定其激活特性的机制知之甚少，无论是在正常健康个体还是癫痫患者中。该提案将使用先进成像、膜片钳记录、基因靶向和光遗传学技术来检查这些机制，重点关注正常动物和癫痫动物模型中齿状回内的单个神经元如何决定激活或保持沉默。从这些研究中得出的见解应该有助于开发出更好、更有效的治疗癫痫和癫痫发展相关并发症的方法。