Clonal Analysis of Neocortical Interneuron Circuit Development

描述（由申请人提供）：哺乳动物新皮层中的几乎所有神经元回路均由多巴胺能兴奋性神经元和GABA能抑制性中间神经元组成。虽然兴奋性神经元负责产生输出，但中间神经元通过通常决定输出的亚型的非凡多样性提供丰富多样的抑制。过去十年的广泛研究揭示了新皮层兴奋性神经元的产生和组织的关键见解。相比之下，我们对新皮层中中间神经元的产生和组织的了解仍然非常有限。例如，尚不清楚单个中间神经元祖细胞是否产生不同亚型的中间神经元，以及源自相同祖细胞的姐妹中间神经元是否被特异性组织化，从而为新皮层中功能回路的形成提供潜在的解剖学基质。为了解决这些基本问题，我们建议进行克隆分析的interneuron生产，迁移和结构和功能组织在新皮层。为了实现我们的目标，我们将开发创新的方法，有效地和选择性地标记中间神经元祖细胞在腹侧端脑-神经节隆起-在克隆密度。我们将使用最先进的成像（例如双光子激光扫描显微镜）和电生理学（例如多电极全细胞膜片钳记录）方法分析被标记的单个中间神经元克隆的产生、迁移以及结构和功能组织，并将这些过程与新皮质中的功能电路形成联系起来。中间神经元畸形和功能障碍与许多神经和心理疾病有关，如癫痫、精神分裂症和自闭症。因此，我们的研究不仅将提供对中间神经元发育的基本见解，并大大推进我们对新皮层功能组织的理解，而且还将揭示许多破坏性脑疾病的病因。1 公共卫生相关性：中间神经元是大脑神经网络的重要组成部分，负责提供多种抑制大脑活动的抑制作用。神经元的畸形和功能障碍与许多神经和心理疾病有关，包括癫痫、精神分裂症和自闭症。我们对哺乳动物大脑中中间神经元的产生和组织的研究将揭示病因学，从而为许多这些毁灭性的大脑疾病的医学治疗提供新的思路。1

DESCRIPTION (provided by applicant): Virtually all neuronal circuits in the mammalian neocortex are composed of glutamatergic excitatory neurons and GABAergic inhibitory interneurons. While excitatory neurons are responsible for generating the output, interneurons provide a rich variety of inhibitions through an extraordinary diversity in subtypes that often determine output. Extensive studies over the past decade have revealed key insights into the production and organization of excitatory neurons in the neocortex. In contrast, our knowledge of interneuron production and organization in the neocortex remains very limited. For example, it is unclear whether a single interneuron progenitor cell gives rise to different subtypes of interneurons and whether sister interneurons originating from the same progenitor cell are specifically organized and thereby provide potential anatomical substrates for the formation of functional circuits in the neocortex. To address these fundamental questions, we propose to perform clonal analysis of interneuron production, migration and structural and functional organization in the neocortex. To achieve our goals, we will develop innovative methods for effectively and selectively labeling interneuron progenitor cells in the ventral telencephalon - the ganglionic eminences - at clonal density. We will analyze the production, migration, and structural and functional organization of individual interneuron clones being labeled using state-of-the-art imaging (e.g. two photon lasers scanning microscopy) and electrophysiology (e.g. multi-electrode whole-cell patch clamp recording) approaches and link these processes to functional circuit formation in the neocortex. Interneuron malformation and dysfunction have been associated with many neurological and psychological disorders, such as epilepsy, schizophrenia and autism. Therefore, our research will not only provide fundamental insights into interneuron development and greatly advance our understanding of the functional organization of the neocortex, but will also shed light on the etiology of many devastating brain disorders. 1 PUBLIC HEALTH RELEVANCE: Interneurons are vital components of neural networks in the brain and are responsible for providing a rich variety of inhibition actions that restrain the brain activity. Malformation and dysfunction of interneruons have been linked to many neurological and psychological illnesses, including epilepsy, schizophrenia and autism. Our studies on interneuron production and organization in the mammalian brain will shed light on the etiology and thereby provide new ideas for the medical treatment of many of these devastating brain disorders. 1