The Development and Integration of Early Born SST-Expressing

早期出生 SST 表达的发展和整合

基本信息

批准号：
8666143
负责人：
GORDON J FISHELL
金额：
$ 35.65万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-11 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8666143
关键词：
Adult Affective Architecture Basal Nucleus of Meynert Behavioral Brain Diseases Cells Cerebral cortex Complex Contralateral Development Disease Epilepsy Etiology Event Excision Gene Expression Genes Genetic Genetic Programming Hippocampus (Brain)Image Interneurons Knockout Mice Limb structure Link Minority Modeling Morphogenesis Mus Mutation Neocortex Neurons Neurotransmitters Phenotype Physiology Play Population Population Heterogeneity Population Study Process Proteins Proxy Reflex action Risk Role Schizophrenia Seizures Sensory Shapes Signal Transduction Sleep Somatostatin Structure Synapses Thalamic structure Time Work barrel cortex cell type clinically relevant critical period gene function hippocampal pyramidal neuron loss of function neocortical nerve supply nervous system disorder novel postnatal research study selective expression transcription factor

项目摘要

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.

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，这些神经元由不同的 GABA 能皮质中间神经元群体整合在一起。在过去的十年中，我们使用桶状皮层作为特征良好的模型，研究了塑造皮质中间神经元发育的起源和遗传因素，以研究皮质中间神经元多样性出现的机制。在本提案中，我们将特别关注新皮质该区域内表达生长抑素的皮质中间神经元的发育。正如我们的初步研究所示，这种皮质中间神经元群体是最先诞生的，并且似乎在建立皮质网络活动中具有独特的作用。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质网络活动联系起来。在本提案中，我们将研究该群体实现成熟连接的发育事件，并研究这些细胞如何促进皮质结构的建立。此外，我们将探讨该群体的成熟如何需要与表达生长抑素的皮质中间神经元选择性表达的转录因子 Satb1。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，表明它充当皮质内早期网络活动与指导该细胞类型发育的遗传程序之间的直接联系。因此，我们还将探索影响这种细胞类型的正常兴奋驱动扰动所产生的表型。总之，这一提议不仅有助于我们理解这种细胞类型的成熟，而且有助于阐明皮质结构是如何建立的。临床相关性：虽然目前的实验主要集中在与皮质发育相关的早期事件的基本水平上，但越来越多的证据表明，皮质中间神经元群体的发育扰动会导致各种情感性脑部疾病，包括精神分裂症、癫痫和自闭症谱系障碍。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 cIN 中有条件去除 Satb1 都会导致行为异常，包括后肢紧握反射和发作间期癫痫样癫痫发作活动，特别是在睡眠期间。因此，这些研究的结果似乎极有可能对我们对情感神经系统疾病的病因及其与异常皮质发育的关系的理解产生直接影响。