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：
9508939
负责人：
GORDON J FISHELL
金额：
$ 33.49万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9508939
关键词：
Adult Affective Architecture Basal Nucleus of Meynert Behavioral Brain Diseases Cell Maturation Cells Cerebral cortex Complex Contralateral Development Disease Epilepsy Etiology Event Excision Gene Expression Genetic Genetic Programming Hindlimb Hippocampus (Brain)Image Interneurons Knockout Mice Link Minority Modeling Morphogenesis Mus Mutation Neocortex Neurons Neurotransmitters Perinatal Pharmacology Phenotype Physiology Play Population Population Heterogeneity Process Proteins Proxy Reflex action Role Schizophrenia Seizures Sensory Shapes Signal Transduction Sleep Somatostatin Structure Synapses Thalamic structure Time Work barrel cortex cell type clinically relevant critical period experimental study gene function hippocampal pyramidal neuron loss of function neocortical nerve supply nervous system disorder novel postnatal programs risk variant selective expression study population transcription factor

项目摘要

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.

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金字塔和星状神经元的网络，并由多样化的GABA能皮质中间神经元集成在一起。在过去的十年中，我们研究了使用枪管皮层作为一种良好的特征模型来塑造皮质中间神经元发展的起源和遗传因素，以研究皮质间神经元多样性出现的机制。在此提案中，我们将特别关注在新皮层该区域内表达生长抑素的皮质中间神经元的发展。如我们的初步研究所示，这种皮质中间神经元的人群是第一个出生的人群，并且似乎在建立皮质网络活动中起着独特的作用。他们通过形成瞬态和早熟的传入和传出连接来实现此功能，从而将新生的上升感觉信息与皮质网络活动联系起来。在此提案中，我们将研究该人群实现其成熟连通性的发展事件，并研究这些细胞如何促进皮质结构的建立。此外，我们将探讨该人群成熟的转录因子SATB1如何选择性地表达表达生长抑素的皮质中间神经元。我们的初步分析表明，编码SATB1蛋白的基因的表达受活性调节，这表明它是皮质内早期网络活性与指导该细胞类型开发的基因程序之间的直接联系。因此，我们还将探索正常兴奋性驱动器撞击这种细胞类型的扰动所产生的表型。这项建议不仅将有助于我们对这种细胞类型的成熟的理解，而且有助于帮助我们在阐明如何建立皮质建筑时。临床相关性：尽管目前的实验集中在基本水平上，但越来越多的证据表明，皮质间神经元种群的发育扰动会导致各种情感脑部疾病，包括精神分裂症，癫痫和ASD。尽管SATB1突变至少尚未引起这些疾病的风险基因，但SATB1无效小鼠和CINS中SATB1的有条件去除会导致行为异常，包括后肢反射和间隔性癫痫发作和癫痫发作的癫痫发作活性，尤其是在睡眠期间。因此，这些研究的发现似乎极有可能与我们对情感神经系统疾病的病因的理解及其与异常皮质发育的关系有关。