Clonal Analysis of Neocortical Interneuron Circuit Development

描述（申请人提供）：哺乳动物新皮层中几乎所有的神经元回路都由谷氨酸能兴奋性神经元和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，但中间神经元通过非同寻常的亚型多样性提供丰富多样的抑制，这些亚型通常决定输出。在过去的十年中，广泛的研究揭示了新皮层中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，目前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，以及来自同一祖细胞的姊妹中间神经元是否被特异性组织，从而为新皮层功能回路的形成提供潜在的解剖基质。为了解决这些基本问题，我们建议对新皮层中中间神经元的产生、迁移以及结构和功能组织进行克隆分析。为了实现我们的目标，我们将开发创新的方法，以克隆密度有效和选择性地标记腹侧端脑（神经节嵴）的中间神经元祖细胞。我们将使用最先进的成像（如双光子激光扫描显微镜）和电生理学（如多电极全细胞膜片钳记录）方法分析单个中间神经元克隆的产生、迁移、结构和功能组织，并将这些过程与新皮层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，我们的研究不仅将为中间神经元的发育提供基本的见解，并极大地推进我们对新皮层功能组织的理解，而且还将阐明许多破坏性大脑疾病的病因。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