The Development and Integration of Early Born SST-Expressing

大脑皮层的复杂功能依赖于广泛分布但高度连接的兴奋性锥体神经元和星状神经元网络，这些神经元通过不同的GABA能皮层中间神经元群体整合在一起。在过去的十年中，我们已经研究了起源和遗传因素，形成皮质中间神经元的发展，使用桶皮质作为一个良好的表征模型，以调查皮质中间神经元多样性出现的机制。在这个提议中，我们将特别关注在新皮层的这个区域内表达生长抑素的皮层中间神经元的发展。正如我们的初步研究所示，这群皮层中间神经元是第一个诞生的，似乎在建立皮层网络活动中具有独特的作用。他们通过形成短暂和早熟的传入和传出连接来实现这一功能，从而将新生的上行感觉信息与皮层网络活动联系起来。在这个建议中，我们将调查的发展事件，这个人口实现其成熟的连接，并检查这些细胞如何有助于建立皮质架构。此外，我们将探讨如何选择性地表达生长抑素表达皮层中间神经元的转录因子Satb1是需要这个人口的成熟。我们的初步分析表明，Satb1蛋白编码基因的表达受活性调节，这表明它是皮质内早期网络活动与指导这种细胞类型发育的遗传程序之间的直接联系。因此，我们也将探讨这种细胞类型的正常兴奋性驱动的扰动所导致的表型。总之，这一提议不仅有助于我们理解这种细胞类型的成熟，而且有助于澄清皮质结构是如何建立的。临床相关性：虽然目前的实验集中在一个基本的水平上的早期事件参与皮质发育，越来越多的证据表明，发展扰动皮质interneuron人口的结果在各种情感性脑障碍，包括精神分裂症，癫痫和ASD。尽管Satb 1突变至少尚未涉及这些疾病的风险基因，但Satb 1缺失小鼠和cIN中Satb 1的有条件去除都会导致行为异常，包括后肢紧握反射和发作间癫痫样癫痫发作活动，特别是在睡眠期间。因此，这些研究的结果极有可能直接影响我们对情感性神经障碍的病因学及其与异常皮层发育的关系的理解。

The complex functions of the cerebral cortex rely on a widely distributed but highly connected networks of excitatory pyramidal and stellate neurons, integrated together by a diverse population of GABAergic cortical interneurons. Over the past decade, we have studied the origin and genetic factors that shape the development of cortical interneurons using the barrel cortex as a well-characterized model to investigate the mechanisms underlying the emergence of cortical interneuron diversity. In this proposal, we will specifically focus on the development of somatostatin-expressing cortical interneurons within this region of the neocortex. As shown in our preliminary studies, this population of cortical interneurons is the first to be born and appear to have a unique role in establishing cortical network activity. They achieve this function by forming both transient and precocious afferent and efferent connections, thus linking nascent ascending sensory information with cortical network activity. In this proposal we will both investigate the developmental events by which this population achieves its mature connectivity and examine how these cells contribute to the establishment of cortical architecture. Moreover, we will explore how the transcription factor Satb1 which is selectively expressed with somatostatin-expressing cortical interneurons is required for the maturation of this population. Our preliminary analysis has revealed that the expression of the gene encoding the Satb1 protein is regulated by activity suggesting that it acts as a direct link between early network activity within the cortex and the genetic program directing the development of this cell type. As such, we will also explore the phenotype resulting from perturbations in the normal excitatory drive impinging on this cell type. Together, this proposal will not only contribute to our understanding of the maturation of this cell type but help in clarifying how cortical architecture is established. Clinical Relevance: Although the present experiments are focused at a basic level on early events involved in cortical development, a growing body of evidence suggests that developmental perturbations in cortical interneuron populations results in a variety of affective brain disorders, including schizophrenia, epilepsy and ASD. Although Satb1 mutations have at least as yet not been implicated a risk gene for these disorders, both Satb1 null mice and the conditional removal of Satb1 in cINs result in behavioral abnormalities including hind- limb clasping reflex and interictal epileptiform seizure activity, particularly during sleep. It thus seems extremely likely that findings from these studies will have direct bearing on our understanding of the etiology of affective neurological disorders and their relationship to aberrant cortical development.