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

描述(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)每天都会增加新的神经元，并被认为参与了海马区的可塑性。然而，由于新生神经元的稀疏分布，使得在有电极的完整回路中很难操纵多个细胞，因此海马神经发生的功能仍然难以捉摸。我们建议使用新的光刺激和光学成像技术来直接和选择性地在完整的海马区和活体中操纵新生神经元群体，并具有高空间和时间分辨率。最近的研究表明，这些成年出生的海马神经元在其成熟的早期阶段表现出更强的兴奋性和高度的增强倾向。一些行为学研究也将学习成绩与未成熟新生神经元的存活联系起来，这表明神经发生在海马区依赖记忆的形成中起着重要作用。然而，新生神经元是否直接参与了海马区的可塑性仍有待确定。这项研究将为海马区处理和记忆形成中的神经发生机制提供第一个电路水平的机制研究。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区的局部网络活动，并且是形成联想记忆的关键要素。新型光门离子通道和活性传感器将被用于促进新生神经元激活的非侵入性和毫秒级控制。在特定的目标1和2中，我们将通过选择性刺激或抑制来表征海马区新生神经元的回路整合。刺激后的电路动态将使用钙成像进行监测。在特定的目标3中，我们将在眨眼跟踪条件作用试验中，通过体内细胞特异性的激活或抑制来确定新生神经元对联想记忆的形成和回忆的贡献。了解新生神经元的功能与翻译再生医学高度相关。这项研究的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为功能神经再生的医学研究提供广泛有用的工具。

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.