Normal and Pathological Function of the Dentate Gyrus

描述（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，在执行认知任务时表现为小亚群放电，与稀疏编码过程一致。稀疏编码是一个随机过程。这可能不适用于齿状回，因为一小部分细胞在多种环境下表现出优先激活，而其他细胞则保持持续沉默，这是一种确定性的放电模式。造成这种情况的机制尚不清楚，但成人大脑中新颗粒细胞的产生可能起了作用。齿状回也调节边缘系统的病理激活。当这一功能受损时，可能会导致癫痫的发展。在癫痫患者中，除了癫痫发作外，还会出现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验证这样一种假设，即稀疏的、确定性的颗粒细胞放电是齿状回内定制抑制功能的特定结果，这在动物中表现出显著的侵蚀

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.