Activity Influence on Adult-Born Neuron Circuit Integration

活动对成年出生神经元回路整合的影响

• 批准号: 7571255
• 负责人: Benjamin R Arenkiel
• 金额: $ 8.45万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571255
• 关键词: Acute; Address; Adult; Biochemical; Biological; Biological Assay; Brain; Brain region; Bromodeoxyuridine; Calcium; Cell Survival; Cells; Complementary DNA; Complex; Data; Dendrites; Dendritic Spines; Development; Due Process; Electrophysiology (science); Excision; Exhibits; Fostering; Gated Ion Channel; Genetic; Genetic Programming; Glutamates; Growth; Hippocampus (Brain); Image; In Situ; In Vitro; Label; Life; Lighting; Maintenance; Mediating; Modeling; Molecular; Molecular Profiling; Morphogenesis; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Nervous system structure; Neurons; Newborn Infant; Oligonucleotides; Pattern; Principal Investigator; Process; Proteins; Receptor Activation; Receptor Signaling; Recombinants; Reporter; Research; Role; Sensory; Series; Signal Transduction; Site; Slice; Small Interfering RNA; Staging; Subfamily lentivirinae; Synapses; Synaptic Transmission; System; Testing; Time; Transgenic Mice; adult neurogenesis; cellular transduction; design; environmental enrichment for laboratory animals; expression vector; granule cell; immunocytochemistry; in vivo; light gated; loss of function; mouse model; nervous system disorder; neural circuit; neural stimulation; neurogenesis; neuron development; neuronal survival; newborn neuron; novel; olfactory bulb; overexpression; presynaptic; programs; promoter; receptor; receptor expression; receptor function; relating to nervous system; research study; response; synaptogenesis

Proper brain function relies on the establishment and maintenance of complex neuronal circuits. The brain's initial wiring diagram is largely determined by developmentally executed genetic programs, but synaptic input ultimately sculpts its final form, function, and plasticity. To deal with a constant barrage of activity input, the adult mammalian brain has evolved the ability to maintain and modify neural circuits through ongoing neurogenesis. This neurogenic potential is primarily restricted to the hippocampus and olfactory bulb, and is influenced by environmental enrichment, sensory stimulation, and even neurological disease. Although the sites and timing of adult neurogenesis have been previously characterized, many of the cellular and molecular mechanisms governing synapse and circuit formation in response to neural activity remain unknown. Investigating this process has been the impeded by the lack of precise control over neuronal stimulation. We have initiated a series of cell biological, electrophysiological, and genetic experiments directed towards manipulating activity in the olfactory bulb while investigating the cell-specific effects on synapse and circuit formation. Using a mouse model that expresses the light-gated ion channel Channelrhodopsin-2 in subsets of neurons in the brain, we are able to selectively activate olfactory bulb mitral cells in a spatially restricted manner. Our preliminary data suggest that mitral cell activation promotes granule cell synaptogenesis and adult-born neuron survival. To address the mechanisms of activity-dependent newborn neuron circuit integration, we have begun to investigate the roles of NMDA receptor signaling. Preliminary data show that NMDA receptor function is important for proper dendrite and spine morphogenesis, suggesting that glutamatergic excitation is critical for synapse formation and cell survival. We propose to investigate the cellular and molecular mechanisms utilized by newborn neurons for synapse formation, circuit integration, and cell survival in response to neural stimulation. The aims outlined in this proposal will establish the framework for a long-term research program designed to implement a multifaceted experimental approach towards investigating proper neuronal development and function.

适当的大脑功能依赖于复杂神经元电路的建立和维护。大脑的初始接线图在很大程度上取决于发育执行的遗传程序，但突触输入最终雕刻其最终形式，功能和可塑性。为了应对持续的活性输入，成年哺乳动物大脑通过持续的神经发生能够维持和修饰神经回路的能力。这种神经源性潜力主要限于海马和嗅球，并且受环境富集，感觉刺激甚至神经系统疾病的影响。尽管先前已经表征了成年神经发生的位点和时间，但许多细胞和分子机制控制着突触和反应对神经活性的回路形成仍然未知。研究这一过程的阻碍，缺乏对神经元刺激的精确控制。我们启动了一系列细胞生物学，电生理和遗传实验，这些实验是针对嗅球的操纵活性的，同时研究了对突触和电路形成的细胞特异性影响。使用小鼠模型，该模型在大脑中神经元的子集中表达光门控通道通道Ropopsin-2，我们能够以空间限制的方式选择性地激活嗅球二尖瓣。我们的初步数据表明，二尖瓣活化促进了颗粒细胞突触发生和成年神经元的存活。为了解决活性依赖性新生儿神经元电路整合的机制，我们开始研究NMDA受体信号传导的作用。初步数据表明，NMDA受体功能对于适当的树突和脊柱形态发生很重要，这表明谷氨酸能激发对于突触形成和细胞存活至关重要。我们建议研究新生神经元用于突触形成，电路整合和细胞存活的细胞和分子机制，以响应神经刺激。本提案中概述的目的将为长期研究计划建立框架，旨在实施多方面的实验方法来研究适当的神经元发展和功能。