THE ROLE OF GENECTIC DETERMINANTS AND ACTIVITY IN THE DEVELOPMENT OF 5HT3AR CORT

项目总结(见说明)： 众所周知，大脑皮层中间神经元(INS)在大脑皮层内具有塑形活动。虽然大部分的努力都是为了 检查这些细胞类型已经集中在MGE来源的篮子和Martinotti细胞上，我们最近 结果表明，CGE来源的神经元群占所有皮质中间神经元的30%，占皮质浅层中间神经元的60%。在这个建议中，我们关注这些人群，我们最近发现这些人群统一表达SHTSaR离子亲性5-羟色胺受体。我们的第一个目标将使用一种新的方法来标记这一群体的单突触连接，并将提供对这些细胞嵌入其中的电路的发展和功能的理解。有了这一点，我们将研究基因和活动在这些中间神经元的产生和整合到发育中的新皮质中的联合作用。这项工作建立在菲舍尔实验室的初步发现基础上，该发现表明，转录因子Prox1对这类中间神经元的指定和成熟是至关重要的。这项建议的第二个目的是探索Prox1在这些中间神经元的发育和规范中的作用。这些研究将通过成像和生理分析检测Prox1基因功能的条件性靶向突变如何影响这一群体的发育、连通性和功能，从而与其对SHT3aR+神经元间发育的影响有关。SHT3aR+中间神经元的一个中心特征是，它们在早期网络活动已经开始的时候整合到大脑皮层。在这项建议的第三个目标中，我们将开始探索这些出生后早期活动对SHT3aR+中间神经元发育的贡献，方法是检测发育过程中兴奋性活动的扰动如何影响五大亚类中间神经元的成熟，以及这如何以及是否导致它们的突触连接发生变化。因此，这些研究将提供对发育基因表达和早期活动如何有助于这些未被研究和未被认识的神经间蛋白亚型成熟的全面理解。

PROJECT SUMMARY (See instructions): Cortical interneurons (INs) are well known to sculpt activity within the cortex. While the majority of effort to examine these cell types has centered on the MGE-derived basket and Martinotti cells, we have recently shown that the CGE-derived populations comprise 30% of all cortical interneurons and represent 60% of the interneurons in the superficial layers of the cortex. In this proposal, we focus on these populations, which we have recently shown uniformly express the SHTSaR ionotropic serotonin receptor. Our first aim will employ a novel method for labeling the monosynaptic connections of this population and will provide an understanding of the development and function of the circuits in which these cells are embedded. With this in hand, we will study the combined contribution of genes and activity in the generation and integration of these interneurons into the developing neocortex. This work builds upon preliminary findings in the Fishell laboratory indicating that the transcription factor Prox1 is central to the specification and maturation of this population of interneurons. The second aim of this proposal is to explore the role of Prox1 in the development and specification of these interneurons. These studies will be related to its impact on SHT3aR+ interneuron development by examining through imaging and physiological analysis how conditional targeted mutation of Prox1 gene function impacts the development, connectivity and function of this population. A central feature that characterizes SHT3aR+ interneurons is that they integrate into the cortex at a time when early network activity has already been initiated. In the third aim of this proposal, we will begin to explore the contributions of these early postnatal activities on SHT3aR+ interneuron development by examining how the maturation of the five major subclasses of interneurons are impacted by perturbations in excitatory activity during development and again how and whether this results in changes in their synaptic connectivity. These studies will thus provide a comprehensive understanding of how developmental gene expression and early activity contribute to the maturation of these understudied and underappreciated interneurcin subtypes.