Mapping Connectivity onto Postnatal-Born Neurons

描述(申请人提供)：哺乳动物的大脑显示出在一生中持续神经发生的非凡能力。这一特征通常发生在大脑的两个区域，即海马齿状回和嗅觉系统。有趣的是，已经发现多种形式的神经活动影响新生神经元的增殖、存活和突触形成的速度。运动、学习和暴露在丰富的感觉环境中，促进持续的神经发生和回路形成，而压力、感觉剥夺和某些神经病理对神经元分裂、回路整合和生存产生负面影响。虽然关于影响哺乳动物大脑中持续神经发生的环境和分子因素已经了解了很多，但关于细胞起源和在电路形成期间对新生神经元进行的不同类型的输入的关键信息仍然缺乏。神经活动是通过新生神经元在发育过程中接受的一系列输入来实现的。到目前为止，突触连接的确切模式、突触形成的时间、提供突触前输入的细胞类型的识别以及通向出生后神经元的突触线索的性质仍然未知。如果我们要利用成人大脑修复的持续神经发生机制，揭示这些输入的身份和性质是至关重要的。本研究的具体目的是：1)确定向新生神经元提供突触前输入的细胞的身份和信号性质；2)确定增强的突触前输入对新生神经元回路整合的影响。这项提案概述了将结合新的分子遗传学方法来标记、绘制和操纵小鼠嗅觉系统中新生神经元的突触前输入的实验，问题是：促进和促进哺乳动物大脑持续回路形成的活动线索的细胞起源和性质是什么？这一建议的主要目的是确定向出生后神经元提供突触前输入的细胞类型，并确定它们在指导突触和回路形成方面的功能。从长远来看，阐明将新生神经元整合到电路中的关键分子因素将显著增强我们对引导成人大脑连接的程序的机制知识，为基于细胞或电路的大脑修复的可能途径提供新的见解。

DESCRIPTION (provided by applicant): The mammalian brain shows a remarkable capacity for continued neurogenesis throughout life. This feature normally occurs in two brain regions, the dentate gyrus of the hippocampus and in the olfactory system. Interestingly, it has been found that multiple forms of neural activity affect the rates of proliferation, survival, and synape formation of newborn neurons. Exercise, learning, and exposure to enriched sensory environments promote continued neurogenesis and circuit formation, whereas stress, sensory deprivation, and certain neuropathologies negatively influence neuronal division, circuit integration, and survival. Although much has been learned about the environmental and molecular factors that influence continued neurogenesis in the mammalian brain, key information regarding the cellular origins and distinct types of inputs that are made onto newborn neurons during periods of circuit formation is lacking. Neural activity is conferred through the repertoire of inputs that newborn neurons receive during their development. To date, the exact patterns of synaptic connectivity, timing of synapse formation, identity of the cel types that provide presynaptic input, and the nature of the synaptic cues onto postnatal-born neurons remain unknown. Revealing the identity and nature of these inputs is essential if we are to harness the mechanisms of continued neurogenesis for adult brain repair. The Specific Aims of this research proposal are to: 1) determine the identity and signaling nature of cells that provide presynaptic input to newborn neurons, and 2) determine the effect of enhanced presynaptic input on newborn neuron circuit integration. This proposal outlines experimentation that will combine novel molecular genetic approaches to mark, map, and manipulate the presynaptic inputs that are made onto newborn neurons in the mouse olfactory system, asking: what are the cellular origins and nature of activity cues that facilitate and promote continued circuit formation in the mammalian brain? The main objective of this proposal is to identify the cell types that provide presynaptic input onto postnatal- born neurons, and to determine their function in guiding synapse and circuit formation. Long-term, elucidating the molecular factors critical for integration of newborn neurons into circuits will significantly enhance our mechanisti knowledge of the programs that guide adult brain wiring, providing novel insights into possible avenues for cell or circuit-based brain repair.