Activity Influence on Adult-Born Neuron Circuit Integration

正常的大脑功能依赖于复杂神经回路的建立和维持。 发育遗传程序在很大程度上决定了大脑最初的线路图，但突触输入 最终塑造了它的最终形态、功能和可塑性。令人惊讶的是，成年哺乳动物的大脑 通过持续的神经发生来维持和修改某些神经回路的能力。这种神经性的 电位主要局限于海马和嗅球，并受环境影响。 丰富，感官刺激，甚至神经疾病。虽然成年的地点和时间 神经发生已经被很好地表征，许多细胞和分子机制， 对神经活动作出反应突触和回路的形成仍然是未知的。一个限制了 我们对这一过程的认识是缺乏对神经元活动的精确控制。为了解决这个 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， 在研究细胞特异性效应的同时操纵嗅球中神经元亚群的活动 突触和回路的形成使用自然气味刺激和表达光门控的小鼠模型， 在脑神经元亚群中，我们发现二尖瓣细胞 活化促进新生颗粒细胞突触发生和成年神经元存活。更好地 了解活动依赖性新生神经元电路整合的细胞机制，我们还 开始研究NMDA受体信号传导的作用。初步数据显示NMDA受体 功能对于正确的树突和棘形态发生、突触功能和神经元存活是重要的。 这项研究的主要目标是更好地理解突触输入是如何与 发育遗传程序来指导突触形成和细胞存活。

Proper brain function relies on the establishment and maintenance of complex neuronal circuits. Developmental genetic programs largely determine the brain's initial wiring diagram, but synaptic input ultimately sculpts its final form, function, and plasticity. Amazingly, the adult mammalian brain has evolved the ability to maintain and modify certain 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 well characterized, many ofthe cellular and molecular mechanisms that govern synapse and circuit formation in response to neural activity remain unknown. One hurdle that has limited our knowledge of this process has been the lack of precise control over neuronal activities. To address this we have initiated a series of cell biological, electrophysiological, and genetic experiments directed towards manipulating the activity of neuronal subsets in the olfactory bulb while investigating the cell-specific effects on synapse and circuit formation. Using natural odor stimulation and a mouse model that expresses the lightgated ion channel Channelrhodopsin-2 in subsets of neurons in the brain, we have found that mitral cell activation promotes newborn granule cell synaptogenesis and adult-born neuron survival. To better understand the cellular mechanisms of activity-dependent newborn neuron circuit integration, we have also begun to investigate the roles of NMDA receptor signaling. Preliminary data show that NMDA receptor function is important for proper dendrite and spine morphogenesis, synaptic function, and neuronal survival. The broad goal of the proposed research is to better understand how synaptic input intersects with developmental genetic programs to guide synapse formation and cell survival.