Roles of the thalamic input and microglia in area-specific regulation of neocortical neurogenesis

哺乳动物的新皮层是高级感觉、运动和认知功能的中心，由以下组成： 几十个功能和解剖学上不同的区域。每个新皮层区域都有一套独特的神经元 分布在六个层次上的类型。这种复杂细胞组织的构建始于特定区域 胚胎发育过程中神经发生的调节。因为它们的区域特定模式 投射，丘脑皮质轴突（TCAs）的理想位置，影响基本的地面计划 通过调节神经前体细胞来控制新皮层。此外，最近的研究发现， 小胶质细胞，大脑中的常驻免疫细胞，调节皮质发育的许多方面，包括 神经发生然而，TCAs和小胶质细胞如何各自调节新皮层中的神经发生尚不清楚。 明白 在这项拨款提案中，我们计划通过以下方式填补这些知识空白：1）开发遗传学方法， 剖析TCA对未来初级感觉皮层中神经元定向神经祖细胞的作用， 2)检验TCA通过TCA衍生的神经肽促进小胶质细胞成熟的新假设 及其受体，其在发育中的皮质中的免疫细胞中特异性表达。 由于小胶质细胞的发育受母体环境的影响很大，我们的研究将有助于阐明 内在的遗传程序和外在的环境因素是如何汇聚在共同的机制上的 控制着皮层结构的基本组织这将有助于更好地了解 许多神经和精神疾病的发病机制源于胚胎发育的异常调节， 神经发生

The mammalian neocortex is the center of higher sensory, motor and cognitive functions, and is composed of dozens of functionally and anatomically distinct areas. Each neocortical area contains a unique set of neuronal types distributed across six layers. Construction of this complex cellular organization begins with area-specific regulation of neurogenesis during embryonic development. Because of their area- specific pattern of projections, the thalamocortical axons (TCAs) are ideally positioned to influence the fundamental ground plan of the neocortex by regulating neural progenitor cells. In addition, recent studies have discovered that microglia, resident immune cells in the brain, modulate many aspects of cortical development including neurogenesis. However, how TCAs and microglia each regulate neurogenesis in the neocortex is poorly understood. In this grant proposal, we plan to fill these knowledge gaps by 1) developing genetic approaches to molecularly dissect the role of TCAs on neuron-committed neural progenitor cells in the future primary sensory cortex and 2) testing the novel hypothesis that TCAs promote the maturation of microglia via a TCA-derived neuropeptide and its receptor that is specifically expressed in immune cells in developing cortex. Because development of microglia is heavily influenced by maternal environment, our research will shed light on how intrinsic genetic programs and extrinsic environmental factors may converge on common mechanisms that control fundamental organization of the cortical architecture. This will lead to a better understanding of the pathogenesis of many neurological and psychiatric disorders that stem from aberrant regulation of embryonic neurogenesis.