Experience-Dependent Synaptogenesis in Adult-Generated Neurons

成人神经元的经验依赖性突触发生

• 批准号: 8313507
• 负责人: Jessica Hotard Chancey
• 金额: $ 3.36万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8313507
• 关键词: AMPA Receptors; Ablation; Address; Adult; Affect; Alzheimer' s Disease; Animal Housing; Animals; Apoptosis; Apoptotic; Area; Brain; Brain region; Cell Death; Cell Survival; Cells; Cognitive; Data; Development; Diabetes Mellitus; Electrophysiology (science); Epilepsy; Ethics; Glutamates; Goals; Hippocampus (Brain); Immunohistochemistry; Impaired cognition; In Vitro; Journals; Label; Learning; Life; Mediating; Memory; Mental Depression; Mentors; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurodegenerative Disorders; Neurons; Newborn Infant; Pathology; Performance; Pharmacology; Physiological; Play; Population; Protocols documentation; Replacement Therapy; Rodent; Role; Schizophrenia; Staging; Stroke; Synapses; Techniques; Testing; Time; Training; Transgenic Mice; Work; adult neurogenesis; base; critical period; dentate gyrus; environmental enrichment for laboratory animals; experience; granule cell; improved; in vivo; insight; meetings; mouse model; nerve stem cell; neurogenesis; newborn neuron; postsynaptic; receptor; research study; response; synaptogenesis; transmission process; voltage

DESCRIPTION (provided by applicant): The dentate gyrus (DG) relays information from the cortex to the hippocampus, a brain region critical for learning and memory. Interestingly, the DG contains a population of neural stem cells that generate new neurons throughout adulthood. The role these cells play in normal hippocampal function is not well understood, but disrupting neurogenesis in the DG disrupts learning, and promoting neurogenesis enhances cognitive performance. Furthermore, neurogenesis is altered in a variety of pathological conditions including diabetes, depression, epilepsy, schizophrenia, and Alzheimer's Disease. In order to contribute to hippocampal function, new neurons must integrate into the existing network. Only a fraction of new dentate granule cells (GCs) survive, while most undergo apoptosis within the first few weeks of maturation. The fate of newborn GCs is influenced by experience. For example, environmental enrichment (EE) increases the survival of adult-generated GCs, but only during an early maturation stage termed the "critical period." Synaptic input has also been shown to be important for survival of newborn GCs, but little is known about how experiences like EE affect synaptic connectivity. Using a transgenic mouse model to identify newborn GCs in the critical period, we have found that EE enhances GABAergic synaptic input to newborn GCs. Housing animals in EE also promotes glutamatergic synaptogenesis. We hypothesize that enhanced GABAergic synaptic depolarization of newborn GCs produced by EE promotes GC survival and excitatory synaptogenesis via the conversion of silent synapses. To address this hypothesis we will 1) investigate how EE increases GABAergic synaptic activity to newborn GCs, 2) test if GABAergic depolarization is necessary and sufficient to convert silent synapses in vitro, and 3) determine whether GABAergic depolarization is necessary for the enhanced survival and excitatory synaptogenesis associated with EE in vivo. These goals will be achieved using a variety of techniques including electrophysiology and immunohistochemistry under the expert guidance of the sponsor. The proposed work will provide a detailed understanding of the mechanisms that promote the survival and integration of endogenous neural stem cells, and could provide pharmacological targets for enhancing or regulating neurogenesis in situations in which neurogenesis is altered, or for improving the efficacy of cell replacement therapies. The training plan for the PI includes participation in yearly seminar speaking opportunities, formal la meetings, journal clubs, presentations at national meetings, formal and informal training in ethical scientific practices, and regular meetings with the mentor. PUBLIC HEALTH RELEVANCE: The proposed study investigates the role of synaptic input on the survival and integration of adult neural stem cells. Understanding the mechanisms underlying the successful integration of neural stem cells may provide targets for enhancing endogenous neurogenesis in pathologies in which neurogenesis is impaired, including depression and Alzheimer's Disease, and may improve neural stem cell replacement therapy for stroke and neurodegenerative diseases.

描述（由申请人提供）：齿状回（DG）将信息从皮质转移到海马，这是对学习和记忆至关重要的大脑区域。有趣的是，DG包含在整个成年期会产生新神经元的神经干细胞群。这些细胞在正常海马功能中起着作用，尚不清楚，但是破坏DG中的神经发生会破坏学习，促进神经发生会增强认知性能。此外，在包括糖尿病，抑郁症，癫痫，精神分裂症和阿尔茨海默氏病在内的多种病理状况下，神经发生也发生了变化。为了促进海马功能，新的神经元必须集成到现有网络中。只有一部分新的牙齿颗粒细胞（GC）存活，而大多数在成熟的头几周内都会凋亡。新生GC的命运受经验的影响。例如，环境富集（EE）增加了成人生成的GC的存活，但仅在早期成熟阶段才被称为“关键时期”。突触输入也已被证明对于新生儿GC的生存至关重要，但是对于EE之类的经验如何影响突触连通性，知之甚少。使用转基因小鼠模型在关键时期识别新生儿GC，我们发现EE增强了GABA能突触输入到新生儿GC。 EE中的外壳动物还促进谷氨酸能突触发生。我们假设EE产生的新生儿GC的GABA能突触增强增强了通过静音突触的转化来促进GC的存活和兴奋性突触发生。为了解决这一假设，我们将1）研究EE如何增加GABA能突触活性为新生GC，2）测试GABA能去极化是否必要且足以在体外转化无声突触，3）确定GABA能去极化对于与EE In In In In In In In In ee相关的增强的生存和兴奋性突触发生所必需。在赞助商的专家指导下，将使用各种技术（包括电生理学和免疫组织化学）来实现这些目标。拟议的工作将详细了解促进内源性神经干细胞存活和整合的机制，并可以在改变神经发生的情况下增加或调节神经发生的药理靶标，或者可以改善细胞替代疗法的疗效。 PI的培训计划包括参加年度研讨会的演讲机会，正式的洛杉矶会议，期刊俱乐部，国家会议上的演讲，道德科学实践的正式和非正式培训以及与导师的定期会议。 公共卫生相关性：拟议的研究调查了突触输入对成年神经干细胞存活和整合的作用。了解神经干细胞成功整合的基础机制可能会为增强神经发生障碍的内源性神经发生的靶标提供损害的内源性神经发生，包括抑郁症和阿尔茨海默氏病，并可能改善神经干细胞替代治疗的中风和神经退行性疾病。