Proliferation, Neural Specification & Brain Function

描述（由申请人提供）：本PPG从皮质的角度研究了大脑形成和功能的遗传调控 中间神经元发育越来越多的证据表明，选择性发育中间神经元缺陷 与神经祖细胞增殖和特化的失败密切相关。细胞功能丧失 周期基因细胞周期蛋白D2导致脑体积减小和中间神经元的选择性丧失，例如小脑 星形和颗粒神经元，而保留篮和高尔基体中间神经元以及投射（浦肯野） 神经元（Ross，Projl）。对大脑皮质VZ神经源性分区的研究表明，GABA能 中间神经元影响皮质神经细胞的增殖和分化（Kriegstein，ProjS）。证据 啮齿动物模型表明，大多数皮质中间神经元起源于内侧神经节隆起 (MGE)（安德森，项目2）;因此，研究中间神经元的发展必须涉及MGE。的目标 该计划是梳理出中间神经元群体对大脑形成的相对贡献， 结构和功能，检查增殖和中间神经元特化对脑的作用 发展 项目1将研究缺乏细胞周期蛋白D2的小鼠大脑中细胞增殖减少的后果， 与小端脑和选择性中间神经元缺陷有关。细胞周期蛋白D2的条件性敲除 进一步限制受影响的神经细胞群将被用来检查特定的动态作用。 神经细胞亚群 项目2将继续研究Shh信号的作用，以1）指定起源于大脑皮层的中间神经元， MGE，和2）（与项目3合作）调节皮质内的增殖。几个Cre-loXP 条件无效将被检查与不同的模式失活Shh或其受体在胚胎 前脑这些小鼠和体外研究将用于探索Shh对皮质神经元的多种作用。 神经发生 项目3将研究MGE的VZ和SVZ中神经原性分区的动态行为 与皮质相比，以确定内在和表观遗传因素如何调节神经发生，以及 分裂模式的区域改变可能导致发育中的中间神经元缺陷。 项目4将研究选择性改变的神经生理学和行为后果， 在项目1和2产生的动物模型中的神经元亚群。 这些项目得到了行政、统计、组织学和定量神经解剖学的支持。 核心A和B中提供的服务。 这些具有高度选择性中间神经元缺陷的遗传小鼠模型使该计划能够检查 神经元亚群对大脑结构、复杂行为和认知功能的贡献。拟议 研究涉及癫痫、精神分裂症、情感障碍和包括自闭症在内的认知障碍。

Description (provided by applicant): This PPG examines genetic regulation of brain formation and function from the perspective of cortical interneuron development. Increasing evidence suggests that selective developmental interneuron deficits are intimately linked with,failure of neural progenitor proliferation and specification. Lost function of the cell cycle gene cyclin D2 results in reduced brain volumes and selective loss of interneurons, e.g. cerebellar stellate and granule neurons, while sparing basket and Golgi interneurons as well as projection (Purkinje) neurons (Ross, Projl). Studies of neurogenic divisions in the cerebral cortical VZ suggest that GABAergic interneurons influence proliferation and differentiation of cortical neural cells (Kriegstein, ProjS). Evidence in rodent models suggests that most cortical interneurons originate from the medial ganglionic eminence (MGE) (Anderson, Proj2); thus investigations of interneuron development must involve MGE. The goal of the Program is to tease out the relative contributions of inteneuronal populations to brain formation, structure and function, examining the role of proliferation and interneuron specification to brain development. Project 1 will examine the consequences of reduced cell proliferation in brains of mice lacking cyclin D2, associated with small telencephalon and selective interneuron deficits. Conditional knockouts of cyclin D2 that further restrict the neural cell populations affected will be used to examine the dynamic role of specific neural subpopulations in brain formation. Project 2 will pursue the roles of Shh signaling to 1) specify cortical interneurons that originate in the MGE, and 2) (collaborating with Project 3) to regulate proliferation within the cortex. Several Cre-loxP conditional nulls will be examined with distinct patterns inactivating Shh or its receptor in the embryonic forebrain. These mice and in vitro studies will be used to explore the multiple roles of Shh on cortical neurogenesis. Project 3 will examine the dynamic behavior of neurogenic divisions in the VZ and SVZ of the MGE compared to cortex to determine how intrinsic and epigenetic factors modulate neurogenesis, and how regional alterations in the pattern of division might contribute to developmental interneuron deficits. Project 4 will examine the neurophysiology and behavioral consequences of the selective alterations of interneuronal subpopulations in animal models produced by Projects 1 and 2. The Projects are supported by administrative, statistical, histological and quantitative neuroanatomical services provided in Cores A and B. These genetic mouse models with highly selective interneuron deficits enable the Program to examine the contributions of neuron subsets to brain structure, complex behaviors and cognitive function. The proposed studies are relevant to epilepsy, schizophrenia, affective disorders and cognitive disorders including autism.