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和星状神经元网络，由多种gaba能皮质中间神经元整合在一起。在过去的十年中，我们研究了形成皮层中间神经元的起源和遗传因素，利用桶状皮层作为一个特征良好的模型来研究皮层中间神经元多样性出现的机制。在这一建议中，我们将特别关注在新皮层的这一区域内表达生长抑素的皮层中间神经元的发育。正如我们的初步研究所显示的，这种皮层中间神经元群是第一个诞生的，似乎在建立皮层网络活动方面具有独特的作用。它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，从而将新生的上升感觉信息与皮层网络活动联系起来。在这个提议中，我们将研究这个群体实现其成熟连接的发育事件，并研究这些细胞如何促进皮层结构的建立。此外，我们将探索在表达生长抑素的皮质中间神经元中选择性表达的转录因子Satb1是如何在这一群体的成熟中发挥作用的。我们的初步分析表明，编码Satb1蛋白的基因的表达受到活性的调节，这表明它在皮层内的早期网络活动和指导这种细胞类型发育的遗传程序之间起着直接的联系。因此，我们也将探讨在正常兴奋驱动冲击这种细胞类型的扰动所导致的表型。总之，这一建议不仅有助于我们理解这种细胞类型的成熟，而且有助于阐明皮层结构是如何建立的。临床意义：虽然目前的实验主要集中在涉及皮质发育的早期事件的基础水平上，但越来越多的证据表明，皮质中间神经元群的发育扰动会导致各种情感性脑障碍，包括精神分裂症、癫痫和ASD。尽管Satb1突变至少尚未被认为是这些疾病的风险基因，但Satb1缺失小鼠和cINs中Satb1的条件移除都会导致行为异常，包括后肢扣扣反射和间发性癫痫发作活动，特别是在睡眠期间。因此，这些研究的发现极有可能直接影响我们对情感性神经障碍的病因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.