Elucidating the interaction between SHH and FGF signaling pathway in postnatal neurogenesis

齿状回(DG)是公认的维持神经干细胞(NSCs)的两个大脑区域之一。 持续产生神经元(称为“神经发生”)，超出发育阶段。新生神经元产生于 DG参与依赖于海马体的学习和记忆。因此，规范机构的因素 发育过程中神经干细胞池的发育及其终生维持对海马区的功能至关重要。 神经干细胞的命运由包括神经回路活动在内的局部微环境因素决定。 癫痫发作引起的海马区高兴奋异常增加大鼠脑内神经发生 成人DG，导致许多NSC的消耗，并导致NSC池的耗尽。尽管 越来越多的证据表明神经元活动调节神经干细胞的动力学，但对其了解甚少 负责任的小生境细胞和连接神经活动和神经干细胞动态的信号分子。类似于 成年DG、发育期DG中的NSCs也可能受活动的影响，但NSCs是否受 在发育中的DG中，在回路建立过程中的早期神经活动还没有被直接解决。 在这笔赠款的前一个资金周期中，我们发现Shh是初始生产的关键利基信号 专门的NSC填充DG并用于其出生后的扩展，以确定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 成年DG的癫痫发作和Shh缺乏的小鼠癫痫诱导的异常神经发生被减弱。 我们以前证明Shh是由齿状脑门中的兴奋性神经元(苔藓细胞)产生的，但 现在将其扩展以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 假设(目标1)来自苔藓细胞的Shh对诱导DG的神经元活动至关重要 神经发生。我们还对发育中的DG的神经元回路进行了研究，发现内嗅觉 皮质向发育中的DG的投射是在出生后第一周建立的，与出现的时间一致 DG中静止的NSCs。我们还发现，神经干细胞接受来自脑内局部神经元的直接信息输入。 在同一时期发展DG。基于这些初步结果，我们形成了第二个假设(对于 目的2)皮质-齿状-神经干细胞通路的发展及其活性控制细胞的增殖状态 发育中的DG中NSCs向静止状态的过渡。

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.