Control of dentate neurogenesis: Shh, mossy cells, activity and seizures

齿状回（DG）是公认的维持神经干细胞（NSCs）的两个脑区之一 持续产生神经元（称为“神经发生”）。新生神经元产生于 DG参与了依赖于海马学习和记忆。因此， 神经干细胞库在发育过程中的变化及其终生维持对海马功能至关重要。 神经干细胞的命运是由局部微环境因素，包括神经回路活动。 癫痫发作引起的海马过度兴奋异常地增加了海马神经元的发生。 成年DG，导致许多NSC的消耗并导致NSC库的耗尽。尽管 神经元活动调节神经干细胞动力学的证据越来越多，但对神经干细胞的动力学机制仍知之甚少。 负责的小生境细胞和信号分子连接神经活动和NSC动力学。类似于 成年DG、发育中的DG中的NSC也可能受到活动的影响，但NSC是否受 在发育中的DG中回路建立期间的早期神经活动尚未被直接解决。 在此赠款的上一个资助周期中，我们发现Shh是初始生产的关键利基信号。 专门的神经干细胞填充DG和其出生后的扩张，以建立NSC池的大小， 成年后的神经发生。在最近的初步数据中，我们发现Shh信号在 癫痫发作在成年DG和癫痫引起的异常神经发生减弱Shh缺陷小鼠。 我们以前发现Shh是由齿状门（苔藓细胞）的兴奋性神经元产生的，但在海马神经元中， 现在扩展了这一点，表明苔藓细胞的活动增强了神经发生。在此基础上，我们制定了 来自苔藓细胞的Shh对DG诱导的神经元活动至关重要的假设（对于目标1） 神经发生我们还研究了发育中DG的神经回路，发现内嗅神经元回路与发育中DG的神经元回路相似。 皮质投射到发育中的DG是在出生后第一周建立的，与外观一致 静止神经干细胞的数量我们还发现，神经干细胞直接接受来自局部神经元的输入， 与此同时，发展中国家。基于这些初步结果，我们提出了第二个假设（ 目的2）皮层-齿状回-神经干细胞回路的发育及其活性控制着神经干细胞的增殖状态， 发展中DG中神经干细胞向静止的过渡。

The dentate gyrus (DG) is one of two brain regions acknowledged to sustain neural stem cells (NSCs) continuously producing neurons (termed “neurogenesis”) beyond development. Newborn neurons produced in the DG are involved in hippocampal-dependent learning and memory. Thus, factors regulating establishment of the NSC pool during development and their life-long maintenance are crucial for hippocampal function. The fate of NSCs is governed by local microenvironmental factors, including neural circuit activity. Hyperexcitation in the hippocampus caused by epileptic seizures aberrantly increases neurogenesis in the adult DG, leading to consumption of many NSCs and results in exhaustion of the NSC pool. Despite accumulating evidence that neuronal activity regulates NSCs dynamics, still little is known about the responsible niche cells and signaling molecules connecting neural activity and NSC dynamics. Similar to the adult DG, NSCs in the developing DG may also be influenced by activity, but whether NSCs are regulated by early neural activity during circuit establishment in the developing DG has not been directly addressed. In the previous funding cycle for this grant, we found that Shh is a key niche signal for the initial production of specialized NSCs populating the DG and for their postnatal expansion to establish the size of the NSC pool for later adult neurogenesis. In more recent preliminary data we have found that Shh signaling is upregulated after seizures in the adult DG and that seizure-induced aberrant neurogenesis is attenuated in Shh deficient mice. We previously showed that Shh is produced from excitatory neurons in the dentate hilus (mossy cells) but have now extended this to show that mossy cell activity enhances neurogenesis. On this basis we have formulated the hypothesis (for Aim 1) that Shh derived from mossy cells is crucial for neuronal activity induced DG neurogenesis. We have also investigated the neuronal circuit in the developing DG and found that the entorhinal cortex projection to the developing DG is established by the first postnatal week coinciding with the appearance of quiescent NSCs in the DG. We have also found that NSCs receive direct inputs from local neurons in the developing DG in this same period. Based on these preliminary results we formulated a second hypothesis (for Aim 2) that development of cortex-dentate-NSCs circuits and their activity control the proliferation state and transition to quiescence of NSCs in the developing DG.