Activity Influence on Adult-Born Neuron Circuit Integration

正常的脑功能依赖于复杂神经元回路的建立和维护。大脑最初的接线图在很大程度上是由发育过程中执行的遗传程序决定的，但突触输入最终塑造了它的最终形式、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，并受环境富集、感觉刺激甚至神经系统疾病的影响。虽然成人神经发生的位置和时间已经被描述，但许多控制突触和神经回路形成的细胞和分子机制对神经活动的反应仍然未知。由于缺乏对神经元刺激的精确控制，对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、电生理学和基因实验，旨在控制嗅球的活动，同时研究细胞对突触和回路形成的特异性影响。利用在大脑神经元亚群中表达光门控离子通道通道视紫红质-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，二尖瓣细胞激活促进颗粒细胞突触发生和成人出生的神经元存活。为了解决活动依赖性新生神经元电路整合的机制，我们已经开始研究NMDA受体信号的作用。初步数据显示，NMDA受体功能对树突和脊柱的正常形态发生至关重要，提示谷氨酸能兴奋对突触形成和细胞存活至关重要。我们建议研究新生神经元在神经刺激下突触形成、电路整合和细胞存活的细胞和分子机制。本提案中概述的目标将建立一个长期研究计划的框架，旨在实施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.