Functional Role of Neurogenesis in Hippocampal Mossy Fiber Sprouting

项目摘要 癫痫是一种慢性疾病，可在各种神经侮辱后发展，包括创伤性大脑 受伤、中风和感染。然而，尽管多年来的研究，癫痫的发展机制 从最初的神经侮辱中脱颖而出仍然难以捉摸。在海马齿状回，癫痫发作驱动 颗粒细胞苔藓状纤维轴突的病理性逆行发芽。尽管萌芽可能有助于 癫痫的发生，苔藓纤维发芽的生理后果尚不清楚。此外，齿状突起 脑回是成人神经发生的场所，成人出生的颗粒细胞可能直接导致苔藓发芽。 纤维，尽管这个问题有广泛的争论和悬而未决的问题。在我们手中，初步数据表明，成年人- 出生的颗粒细胞确实会产生发芽的苔藓纤维，这些纤维在内部分子层形成大的突起。 齿状回的。此外，成熟颗粒细胞的全细胞膜片钳记录表明 这些成年出生的神经元在功能上参与了经常性的兴奋回路。这个项目的目标是 更好地了解促进海马区过度兴奋的机制，并提供有针对性的 未来预防癫痫发生的治疗机制。我们的总体假设是成体出生的颗粒 细胞提供了苔藓纤维发芽的大部分，这些异常的突触产生了经常性的微回路 在海马体中驱动失控的兴奋。这一假说将用匹罗卡品进行检验。 癫痫模型及小鼠年龄相关颗粒细胞群的转基因标记。苔藓纤维发芽 将通过颗粒细胞的免疫荧光染色进行定量，并将使用全细胞电生理学 利用颗粒细胞光遗传刺激检测循环回路和询问萌发的突触 一群人。这项建议的具体目的是独立检查成人出生的颗粒细胞的贡献。 苔藓纤维发芽和发芽突触的生理特性。此外，这项建议 研究沉默发芽的苔藓纤维是否可以减弱海马区的过度兴奋性，即 与癫痫有关。综上所述，本提案旨在从功能上理解电路重排 影响癫痫的海马体，这样未来的治疗就可以针对癫痫的疾病，而不是 症状。

Project Summary Epilepsy is a chronic condition that can develop after various neurological insults, including traumatic brain injury, stroke, and infection. However, despite years of study, the mechanism for the development of epilepsy from an initial neurological insult has remained elusive. In the hippocampal dentate gyrus, seizures drive pathologic retrograde sprouting of granule cell mossy fiber axons. Although sprouting may contribute to epileptogenesis, the physiologic consequences of mossy fiber sprouting are unknown. Additionally, the dentate gyrus is a locus for adult neurogenesis and adult-born granule cells might directly give rise to sprouted mossy fibers, though this is widely debated and unresolved. In our hands, preliminary data has indicated that adult- born granule cells do give rise to sprouted mossy fibers, which form large boutons in the inner molecular layer of the dentate gyrus. Moreover, whole-cell patch clamp recordings from mature granule cells indicate that these adult-born neurons functionally contribute to recurrent excitatory circuitry. The goal of this project is to better understand mechanisms that contribute to hippocampal hyperexcitability and provide a targetable mechanism for future treatments to prevent epileptogenesis. Our overall hypothesis is that adult-born granule cells provide the bulk of mossy fiber sprouting and that these aberrant synapses create recurrent microcircuits that drive runaway excitation within the hippocampus. This hypothesis will be tested using the pilocarpine model of epilepsy and transgenic labeling of age-defined cohorts of granule cells in mice. Mossy fiber sprouting will be quantified by immunofluorescent staining of granule cells, and whole-cell electrophysiology will be used to detect recurrent circuits and interrogate the sprouted synapse using optogenetic stimulation of granule cell cohorts. The specific aims of this proposal independently examine the contribution of adult-born granule cells to mossy fiber sprouting and the physiological properties of a sprouted synapse. Furthermore, this proposal investigates whether silencing of sprouted mossy fibers can attenuate the hippocampal hyperexcitability that is associated with epilepsy. Taken together, this proposal aims to understand circuit rearrangements functionally affect the epileptic hippocampus, so that future treatments can target the disease of epilepsy, rather than the symptoms.