Normal and Pathological Function of the Dentate Gyrus

齿状回作为海马体的关键调节入口点，翻译海马体的功能。 内侧内嗅皮层神经元高度活跃的编码语言， 海马功能的特征编码。这种齿状回介导的翻译 对于CNS中信息处理的许多方面至关重要。下面的电路 负责齿状回内这种活动水平转换的机制主要是 未知，但局部回路抑制神经元被假设发挥重要作用。的 齿状回还具有调节边缘系统的病理性激活的功能， 异常活动从内嗅皮层传递到海马体。过滤器丢失或 门控功能可能有助于癫痫发作的产生，这是癫痫的标志。在这 建议，我们将利用最先进的成像，膜片钳，化学遗传学和转基因 技术来测试的假设，稀疏放电特性的特点齿状 颗粒细胞在局部回路中产生，这些机制中的退化 有助于癫痫发作易感性和认知共病特征性癫痫。 我们建议确定介导齿状颗粒细胞活化的细胞特性， 了解负责控制齿状颗粒细胞激活的中间神经元的身份， 研究癫痫患者颗粒细胞稀疏放电退化的机制 动物，最后，恢复正常的认知功能，在动物与癫痫使用 对颗粒细胞放电水平的化学遗传学操纵。我们对它的机制知之甚少 介导海马齿状回神经元的放电特性， 信息编码，甚至更少关于癫痫如何可能侵蚀这一关键方面的信息。 海马体产生的认知功能。除了癫痫发作， 癫痫表现出严重的学习和记忆缺陷。了解癫痫如何 发展改变了边缘系统内的电路特性，这可能不仅对 针对癫痫发作改善的新疗法，但也在开发新的治疗方法， 减少伴随癫痫发展的共病情况。

The dentate gyrus serves as a critical regulatory entry point to the hippocampus, translating the highly active coding language of medial entorhinal cortical neurons to the distinct, sparse encoding that is characteristic of hippocampal function. This dentate gyrus-mediated translation is vital to many aspects of information processing in the CNS. The underlying circuit mechanisms responsible for this activity level transformation within the dentate gyrus are largely unknown, but local circuit inhibitory neurons are hypothesized to play an important role. The dentate gyrus also functions to regulate pathological activation of the limbic system, restricting relay of aberrant activity from the entorhinal cortex to the hippocampus. Loss of this filter or gating function could contribute to the generation of seizures, the hallmark of epilepsy. In this proposal, we will utilize state of the art imaging, patch clamp, chemogenetic, and transgenic techniques to test the hypotheses that that the sparse firing properties characteristic of dentate granule cells are generated within the local circuit, and that degradation in these mechanisms contributes both to seizure predisposition and cognitive comorbidities characterizing epilepsy. We propose to determine the cellular properties that mediate dentate granule cell activation, learn the identity of interneurons responsible for the control of dentate granule cell activation, study the mechanisms responsible for degradation in granule cell sparse firing in epileptic animals, and finally, restore normal cognitive function in animals with epilepsy using chemogenetic manipulation of granule cell firing levels. We know little about the mechanisms mediating the firing properties of neurons in the hippocampal dentate gyrus responsible for information coding, and even less about how epilepsy may erode this critical aspect of the cognitive functions emerging from the hippocampus. In addition to seizures, patients with epilepsy exhibit severe deficits in learning and memory. Understanding how epilepsy development alters circuit properties within the limbic system may be important not only in targeting new therapies for seizure amelioration, but also in developing new treatments to reduce comorbid conditions accompanying epilepsy development.