Synapses and Circuits in the Hippocampus

描述（申请人提供）：突触可塑性被广泛认为是学习、记忆和适应环境能力的基础。在单个神经元或人类行为的层面上，很明显，我们年轻时的可塑性更强。然而，在成年哺乳动物的大脑中，可塑性、修复和再生的潜力尚未开发，这一点可以从几个大脑区域新神经元的诞生中得到证明。这些问题对于理解和潜在治疗神经发育障碍、自闭症和智力迟钝，以及导致神经丧失或退化的疾病（如中风、癫痫、脑和脊髓创伤、帕金森病和阿尔茨海默病）至关重要。该项目的长期目标是了解海马体中单个突触水平的回路形成机制。许多实验努力都是针对神经发生的早期阶段，而对于成人产生的神经元如何整合到成人大脑的功能网络中，我们所知甚少。至于神经发育，了解成人新神经元的功能整合是一项艰巨的任务，因为假设有数百个分子在空间和时间上精确的顺序。如何在完整的动物身上解决这个巨大的问题，同时又能接触到单细胞和突触呢？该项目利用一种新型转基因小鼠来跟踪树突和突触的发育，因为新的神经元离开了它们的生态位，并整合到齿状回的成年电路中。初步数据表明，这一过程发生在不同的阶段，在一段时间内，树突生长有限，只有gaba能突触，几周后，树突生长和新的兴奋性突触。该项目将使用电生理学和细胞成像技术来绘制新神经元融入成人网络时的输入和输出图，无论是在正常情况下，还是在运动和癫痫发作等扰动之后。调控这一阶段特异性发育的分子的作用将在转基因小鼠中使用特异性启动子进行选择性标记，并在体内使用病毒介导的基因操作进行测试。检测将使用生化和分子方法以及脑切片生理学。追踪这些不同阶段的能力也将用于测试细胞粘附分子在突触成熟中的作用。项目的叙述

DESCRIPTION (provided by applicant): Synaptic plasticity is widely regarded as the basis for learning, memory, and our ability to adapt to our surroundings. At the level of single neurons or at the level of human behavior, it is clear that plasticity is more robust when we are young. However there is untapped potential for plasticity, repair and regeneration in the adult mammalian brain, as evidenced by the birth of new neurons in several brain regions. These issues are central to the understanding and potential treatment of neurodevelopmental disorders, autism and mental retardation, as well as conditions that result in neural loss or degeneration such as stroke, epilepsy, brain and spinal cord trauma, Parkinson's disease, and Alzheimer's disease. The long-term goal of this project is to understand the mechanisms of circuit formation at the level of single synapses in the hippocampus. Much experimental effort has been directed at the very early period of neurogenesis, whereas much less is known about the integration of adult-generated neurons into functional networks in the adult brain. As for neural development, understanding the functional integration of new neurons in the adult is a daunting task because of the presumed contribution of hundreds of molecules in a spatially and temporally precise sequence. How does one approach this immense problem in the intact animal, yet gain access to single cells and synapses? This project makes use of a novel transgenic mouse to track the development of dendrites and synapses as new neurons leave their niche, and integrate into the adult circuitry of the dentate gyrus. Preliminary data suggests that this process occurs in distinct stages with a period of limited dendrite outgrowth and exclusively GABAergic synapses, followed weeks later by additional dendritic growth and new excitatory synapses. The project will use electrophysiology and cell imaging to chart the inputs and outputs as new neurons integrate into the adult network, both in normal conditions and following perturbations such as exercise and epileptic seizures. The role of molecules that regulate this stage-specific development will be tested using selective marking with specific promoters in transgenic mice, and viral-mediated gene manipulation in vivo. Assays will use biochemical and molecular methods as well as brain slice physiology. The ability to track these distinct stages will also be used to test the role of cell adhesion molecules in synapse maturation.Project Narrative Many neuropsychiatric illnesses cause loss of nerve cells and/or disruption of connections between nerve cells (synapses). This project takes advantage of a unique mouse model to examine the integration of adult- generated (new) neurons into synaptic networks in the hippocampus, thus providing access at the single nerve cell level to mechanisms of synapse formation, repair and regeneration in the brain. These issues are central to the understanding and potential treatment of neurodevelopmental disorders, autism, mental retardation and mood disorders, as well as conditions that result in neural loss or degeneration such as stroke, epilepsy, brain and spinal cord trauma, Parkinson's disease, and Alzheimer's disease.