The Development and Integration of Early Born SST-Expressing

描述（由申请人提供）：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，形成皮层中间神经元的发展，使用桶皮质作为一个良好的表征模型，以调查皮层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Satb 1是需要这个人口的成熟。我们的初步分析表明，Satb 1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， 大脑皮层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的条件性去除均导致行为异常，包括后肢紧握反射和发作间癫痫样发作活动，特别是在睡眠期间。因此，这些研究的结果极有可能对我们理解情感性神经障碍的病因及其与异常皮层发育的关系有直接的影响。 公共卫生相关性：在这个建议中，我们使用遗传学，成像和生理学的组合来研究生长抑素皮质中间神经元（SST-cINs）在皮质网络的发展中发挥的作用。正如我们的初步研究所示，SST-cINs似乎要经过一个关键时期，在此期间它们都接受并形成广泛的突触连接。通过这一点，似乎SST-cINs在网络活动的建立中发挥了以前未被怀疑的作用。除了描述这些意料之外的发育事件，我们还研究了一种新的转录因子Satb 1的作用，Satb 1对发育过程中的细胞凋亡是必不可少的。 这个中间神经元群体的发展。最后，我们探讨了活动在塑造这一人群的发展和代理出现的皮层网络功能的作用。

DESCRIPTION (provided by applicant): 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 studie will have direct bearing on our understanding of the etiology of affective neurological disorders and their relationship to aberrant cortical development. PUBLIC HEALTH RELEVANCE: In this proposal, we use a combination of genetics, imaging and physiology to study the role somatostatin cortical interneurons (SST-cINs) play in the development of cortical networks. As shown in our preliminary studies, SST-cINs appear to transit through a critical period during which they both receive and form widespread synaptic connections. Through this it appears that SST-cINs play a previously unsuspected role in the establishment of network activity. In addition to describing these unanticipated developmental events, we examine the contribution of a novel transcription factor Satb1 that is essential for the development of this interneuron population. Finally, we explore the role of activity in both shaping the development of this population and by proxy the emergence of cortical network function.