Decoding the Function of Adult Neurogenesis: From Neural Circuits to Behavior

描述（由申请人提供）：成人的大脑是不断变化的。成年哺乳动物大脑的齿状回（DG）每天都有新的神经元加入，并被认为与海马可塑性有关。然而，海马神经发生的功能仍然是难以捉摸的，因为新生的神经元分布稀疏，使得很难操纵超过几个细胞在完整的电路与电极。我们建议使用新的光刺激和光学成像技术直接和选择性地操纵新生神经元群体在完整的海马电路和体内，具有高的空间和时间分辨率。最近的研究表明，这些成年出生的海马神经元表现出更大的兴奋性和高倾向的增强在其成熟的早期阶段。一些行为学研究也将学习表现与未成熟新生神经元的存活相关联，表明神经发生在大脑皮层依赖的记忆形成中起着重要作用。然而，新生神经元是否直接参与海马可塑性仍有待确定。这项研究将提供第一个关于海马处理和记忆形成中神经发生的回路水平机制研究。我们假设新生神经元招募特定类别的中间神经元来调节海马中的局部网络活动，并且是联想记忆形成的关键要素。新型光门控离子通道和活动传感器将用于促进新生神经元激活的非侵入性和毫秒控制。在具体目标1和2中，我们将通过选择性刺激或抑制来表征海马新生神经元的电路整合。将使用钙成像监测刺激后电路动态。在具体目标3中，我们将确定新生神经元的贡献，形成和回忆的联想记忆细胞特异性在体内激活或抑制眨眼跟踪条件试验。了解新生神经元的功能与转化再生医学高度相关。本研究结果将有助于指导神经干细胞移植研究。此外，本研究开发的技术将成为功能性神经再生医学研究的广泛有用的工具。

DESCRIPTION (provided by applicant): The adult brain is constantly changing. New neurons are added daily in the dentate gyrus (DG) of the adult mammalian brain and are thought to be involved in hippocampal plasticity. However, the function of hippocampal neurogenesis remains elusive because newborn neurons are sparsely distributed, making it difficult to manipulate more than a few cells in intact circuit with electrodes. We propose to use novel photostimulation and optical imaging technologies to manipulate newborn neuron populations directly and selectively in intact hippocampal circuits and in vivo, with high spatial and temporal resolution. Recent studies indicate that these adult-born hippocampal neurons exhibit greater excitability and a high propensity for potentiation during early stages of their maturation. Several behavioral studies have also correlated learning performance with the survival of immature newborn neurons, suggesting that neurogenesis has a significant role in hippocampal-dependent memory formation. Yet whether newborn neurons directly participate in hippocampal plasticity remains to be determined. This study will provide the first circuit-level mechanistic study of neurogenesis in hippocampal processing and memory formation. We hypothesize that newborn neurons recruit specific classes of interneurons to modulate local network activity in the hippocampus and are crucial elements for associative memory formation. Novel light-gated ion channels and activity sensors will be used to facilitate noninvasive and millisecond-control of newborn neuron activation. In Specific Aims 1 and 2 we will characterize the circuit integration of hippocampal newborn neurons by selective stimulation or inhibition. The post-stimulation circuit dynamics will be monitored using calcium imaging. In Specific Aim 3 we will determine the contribution of newborn neurons to formation and recall of associative memory by cell-specific in vivo activation or inhibition during eyeblink trace conditioning trials. Understanding the functional of newborn neurons is highly relevant to translational regenerative medicine. The results from this study will help guide neural stem cell transplantation studies. Also, the technologies developed in this study will be a widely useful tool for medical research in functional neural regeneration.