Functional integration of inhibitory interneuron progenitors in the adult brain

成人大脑中抑制性中间神经元祖细胞的功能整合

基本信息

批准号：
8311375
负责人：
Robert F Hunt
金额：
$ 4.92万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311375
关键词：
Accounting Acute Adult Affect Alzheimer&apos s Disease Animals Autistic Disorder Brain Brain Diseases Brain region Cell Therapy Cell Transplantation Cells Characteristics Cholecystokinin Confocal Microscopy Craniocerebral Trauma Data Development Electrophysiology (science)Embryo Epilepsy Fellowship Goals Hippocampus (Brain)Human Image Interneurons Laboratories Learning Medial Memory Mental disorders Methods Modeling Molecular Mood Disorders Morphology Mus Neonatal Nerve Degeneration Neurobiology Neurons Parvalbumins Pattern Phenotype Physiological Population Property Replacement Therapy Research Reverse Transcriptase Polymerase Chain Reaction Rodent Role Schizophrenia Scientist Seizures Series Slice Somatostatin Stem cells Synapses Techniques Telencephalon Therapeutic Transplantation Vasoactive Intestinal Peptide biocytin calretinin cell motility clinical application dentate gyrus design gamma-Aminobutyric Acid injured interest migration nerve stem cell nervous system disorder neural circuit patch clamp postnatal postsynaptic progenitor programs research study synaptic inhibition way finding

项目摘要

DESCRIPTION (provided by applicant): Inhibitory interneurons perform important roles in regulating cortical network function, and their loss is associated with a number of neurological and psychiatric disorders. As such, transplantation of inhibitory neuronal progenitor cells might be a useful method to restore deficits in inhibition in the diseased brain. Our laboratory recently demonstrated that progenitor cells derived from the medial ganglionic eminence can migrate, differentiate into GABAergic interneurons, and suppress spontaneous seizures in a developmental epilepsy model. Despite these recent advances in transplantation strategies, the effect of inhibitory neural progenitor cell subtypes derived from other regions of the embryonic telencephalon on existing host circuitry remains largely unknown, especially after transplant into the adult brain. In this postdoctoral fellowship proposal, I will determine how GABA-progenitor cells derived from the caudal ganglionic eminence alter inhibitory circuitry after transplant into the adult dentate gyrus. Two specific aims are proposed, to determine: (1) progenitor cell migration and phenotypes of GABAergic subtypes generated after transplant into the adult hippocampus, and (2) how these new interneurons alter existing synaptic circuitry in the dentate gyrus. Electrophysiological results will be correlated with cellular, molecular, and anatomical characteristics. This study will provide detailed information about the synaptic connectivity of GABAergic progenitor cells after transplant into the adult brain. PUBLIC HEALTH RELEVANCE: A number of neurological disorders involve the loss of inhibitory interneurons, and a transplantation method to generate new cortical interneuron subtypes in affected brain regions might be a useful therapeutic approach. I will determine how embryonic inhibitory neural progenitor cells integrate into existing circuits after transplant into the adult hippocampus. By determining the synaptic connections formed by these cells, we will be able to develop methods for cortical interneuron replacement therapies to restore normal function in the human diseased brain.

描述（由申请人提供）：抑制性中间神经元在调节皮质网络功能中发挥重要作用，其丧失与许多神经和精神疾病相关。因此，抑制性神经元祖细胞的移植可能是恢复患病大脑抑制缺陷的有用方法。我们实验室最近证明源自内侧神经节隆起的祖细胞可以迁移、分化为 GABA 能中间神经元，并在发育性癫痫模型中抑制自发性癫痫发作。尽管移植策略最近取得了这些进展，但来自胚胎端脑其他区域的抑制性神经祖细胞亚型对现有宿主电路的影响仍然很大程度上未知，特别是在移植到成人大脑后。在这个博士后奖学金提案中，我将确定来自尾神经节隆起的 GABA 祖细胞在移植到成人齿状回后如何改变抑制回路。提出了两个具体目标，以确定：（1）移植到成年海马后产生的祖细胞迁移和 GABA 能亚型的表型，以及（2）这些新的中间神经元如何改变齿状回中现有的突触回路。电生理学结果将与细胞、分子和解剖学特征相关。这项研究将提供有关 GABA 祖细胞移植到成人大脑后突触连接的详细信息。公共卫生相关性：许多神经系统疾病涉及抑制性中间神经元的丧失，在受影响的大脑区域产生新的皮质中间神经元亚型的移植方法可能是一种有用的治疗方法。我将确定胚胎抑制性神经祖细胞在移植到体内后如何整合到现有的回路中成人海马体。通过确定这些细胞形成的突触连接，我们将能够开发皮质中间神经元替代疗法的方法，以恢复人类患病大脑的正常功能。