Activity Influence on Adult-Born Neuron Circuit Integration

大脑的正常功能有赖于复杂神经元回路的建立和维持。大脑最初的接线图在很大程度上是由发育执行的遗传程序决定的，但突触输入最终决定了它的最终形式、功能和可塑性。为了处理持续不断的活动输入，成年哺乳动物的大脑已经进化出通过持续的神经发生来维持和修改神经回路的能力。这种神经源性潜能主要局限于海马体和嗅球，并受到环境丰富、感觉刺激甚至神经疾病的影响。尽管成体神经发生的部位和时间已经被描述，但许多调控突触和回路形成的细胞和分子机制仍不清楚。由于缺乏对神经元刺激的精确控制，这一过程的研究一直受到阻碍。我们已经启动了一系列细胞生物学、电生理学和遗传学实验，旨在操纵嗅球的活动，同时研究细胞特异性对突触和电路形成的影响。利用在大脑神经元亚群中表达光门控离子通道Channel视紫红质-2的小鼠模型，我们能够以空间受限的方式选择性地激活嗅球二尖瓣细胞。我们的初步数据表明，二尖瓣细胞的激活促进了颗粒细胞的突触发生和成年神经元的存活。为了解决活动依赖的新生神经元回路整合的机制，我们已经开始研究NMDA受体信号转导的作用。初步数据显示，NMDA受体功能对正常的树突和棘细胞形态发生非常重要，提示谷氨酸能兴奋对突触的形成和细胞的存活至关重要。我们建议研究新生神经元在神经刺激下用于突触形成、电路整合和细胞存活的细胞和分子机制。这项提案中概述的目标将为长期研究计划建立框架，旨在实施一种多方面的实验方法来研究适当的神经元发育和功能。

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.