Synapses and Circuits in the Hippocampus

描述(申请人提供)：突触的可塑性被广泛认为是学习、记忆和我们适应周围环境的能力的基础。在单个神经元的水平上，或者在人类行为的水平上，很明显，当我们年轻的时候，可塑性更强大。然而，成年哺乳动物的大脑还有尚未开发的可塑性、修复和再生的潜力，正如几个脑区新神经元的诞生所证明的那样。这些问题对于了解和可能治疗神经发育障碍、自闭症和精神发育迟缓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、帕金森氏病和阿尔茨海默病是至关重要的。该项目的长期目标是在海马区单个突触的水平上了解回路形成的机制。许多实验工作都是针对神经发生的非常早期阶段，而对成人产生的神经元与成人大脑功能网络的整合知之甚少。至于神经发育，理解成人新神经元的功能整合是一项艰巨的任务，因为据推测，成百上千的分子在空间和时间上都有精确的序列。如何在完好无损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？这个项目利用一种新型的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壁龛，并整合到齿状回的成年回路中。初步数据表明，这一过程发生在不同的阶段，树突生长有限，仅有GABA能突触，几周后又有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来绘制新神经元整合到成人网络中时的输入和输出，无论是在正常条件下还是在运动和癫痫发作等扰动之后。调控这一特定阶段发育的分子的作用将通过在转基因小鼠中使用特定启动子的选择性标记和体内病毒介导的基因操作来测试。化验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被用来测试细胞黏附分子在突触成熟中的作用。 许多神经精神病学疾病会导致神经细胞丢失和/或神经细胞之间的连接中断(突触)。该项目利用一种独特的小鼠模型来研究成年产生的(新的)神经元与海马区突触网络的整合，从而在单个神经细胞水平上提供进入大脑突触形成、修复和再生机制的途径。这些问题对于了解和可能治疗神经发育障碍、自闭症、精神发育迟滞和情绪障碍，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、帕金森氏症和阿尔茨海默病，都是至关重要的。

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.