Normal and Pathological Function of the Dentate Gyrus

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，齿状颗粒细胞，在执行认知任务的过程中表现出小的亚群放电，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，因为小群体的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。对此负责的机制是完全未知的，但成年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，还有与齿状回和其他海马结构损伤相关的认知缺陷。在这项提议中，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这一假设，即颗粒细胞的稀疏的、确定性的放电是齿状回内定制的抑制功能的特定结果，并且这在动物中表现出显著的侵蚀， 癫痫我们建议表征网络发射在齿状回，确定这些放电特性的成年出生的颗粒细胞的贡献，并检查癫痫动物的齿状网络激活。关于齿状回中介导细胞激活的机制以及癫痫发展如何侵蚀这些过程知之甚少。除了癫痫发作之外，癫痫患者还表现出严重的认知共病，包括情感、情绪以及学习和记忆的缺陷，通常被认为是边缘系统功能。了解癫痫的发展如何改变边缘回路的特性，对于针对癫痫发作改善的新疗法和开发治疗方法以减少与癫痫发作疾病相关的共病状况都很重要。

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.