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

• 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
• 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' 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

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，移植抑制性神经元祖细胞可能是一种有用的方法，以恢复缺陷的抑制在患病的大脑。我们的实验室最近 证明了来源于内侧神经节隆起的祖细胞可以迁移，分化成GABA能中间神经元，并抑制发育性癫痫模型中的自发性癫痫发作。尽管移植策略的这些最新进展，抑制性神经祖细胞亚型来自胚胎端脑的其他区域对现有的主机电路的影响仍然在很大程度上是未知的，特别是在移植到成年人的大脑。在这个博士后奖学金的建议，我将确定如何GABA祖细胞从尾神经节隆起移植到成人齿状回后改变抑制电路。提出了两个具体的目标，以确定：（1）祖细胞迁移和GABA能亚型移植到成年海马后产生的表型，以及（2）这些新的中间神经元如何改变现有的突触在齿状回电路。电生理结果将与细胞、分子和解剖特征相关。这项研究将提供有关GABA能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，并且在受影响的脑区域中产生新的皮质中间神经元亚型的移植方法可能是有用的治疗方法。我将确定胚胎抑制性神经祖细胞在移植到 成年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。