Newborn Neurons in the Adult Hippocampal Network

 描述（由申请人提供）：神经发生持续存在于所有成年哺乳动物（包括人类）的齿状回中。神经的产生受到许多生理和病理条件的干扰，并且神经发生的选择性操纵表明，成年出生的神经元有助于海马依赖性行为。尽管指导神经发生的细胞生物学过程的知识越来越多，但对可能赋予成年人出生的神经元的小群体以促进海马功能的生理特性知之甚少。一种可能性是，不断更新的未成熟神经元群体表现出与先前存在的神经元群体不同的特性，从而产生独特的功能。虽然相当多的注意力集中在内在兴奋性的瞬时差异，不同的电路的潜在后果还没有被探讨。该项目的目标是确定成熟过程中突触连接的变化如何影响齿状神经元的激活，从而可能允许未成熟和成熟的神经元处理海马网络活动的不同组成部分。齿状神经元接受两种主要的兴奋性传入投射;起源于内嗅皮层的穿孔通路和海马本身内的门苔藓细胞产生的联合/连合通路。我们将使用体外切片生理学，各种转基因小鼠模型和光遗传学来解决如何改变突触连接和内在特性控制在成熟的进行性阶段的招聘。首先，我们将重点了解控制兴奋性驱动和突触整合的穿通通路和联合/连合通路的机制（目标1和2）。这些单细胞研究将扩展到测试选择性通路刺激在突触和回路水平的功能后果（目标3）。我们将超越电路映射，以了解阶段特异性突触特性如何与内在兴奋性相互作用，以决定皮质和海马传入活动的整合。这些目标的结果将揭示突触连接如何有助于未成熟神经元参与齿状回电路，并提供洞察成年神经发生的潜力，以产生一个异质群体的齿状回神经元，可以发挥不同的作用，海马功能。了解成人出生的神经元的生理功能是解剖成人神经发生的意义和目的的重要组成部分，成人神经发生是大脑可塑性的一种戏剧性形式，可能是许多大脑疾病的治疗目标。

 DESCRIPTION (provided by applicant): Neurogenesis persists in the dentate gyrus of all adult mammals, including humans. Neural production is perturbed by many physiological and pathological conditions, and selective manipulation of neurogenesis suggests that adult born neurons contribute to hippocampal-dependent behaviors. Despite growing knowledge of the cell biological processes directing neurogenesis, less is known about the physiological properties that may endow the small population of adult born neurons to contribute to hippocampal function. One possibility is that the continually renewing population of immature neurons exhibits distinct properties from the larger population of pre-existing neurons, resulting in unique functionality. Although considerable attention has focused on transient differences in intrinsic excitability, the potential consequences of distinct circuitry have not been explored. The goal of this project is to determine how changes in synaptic connectivity across maturation affect activation of dentate neurons, potentially allowing immature and mature neurons to process distinct components of hippocampal network activity. Dentate neurons receive two main excitatory afferent projections; the perforant path originating from the entorhinal cortex and the associational/commissural pathway arising from hilar mossy cells within the hippocampus itself. We will use in vitro slice physiology, a variety of transgenic mouse models and optogenetics to address how changing synaptic connectivity and intrinsic properties control recruitment at progressive stages of maturation. First we will focus on understanding the mechanisms controlling excitatory drive and synaptic integration of the perforant path and associational/commissural pathways (Aims 1 & 2).These single cell studies will be extended to test functional consequences of selective pathway stimulation at the synaptic and circuit level (Aim 3). We will go beyond circuit mapping to understand how stage-specific synaptic properties interact with intrinsic excitability to dictate integration of cortical and hippocampal afferent activity. Together the results of these Aims will reveal how synaptic connectivity contributes to the participation of immature neurons in dentate circuitry and provide insight into the potential for adult neurogenesis to produce a heterogeneous population of dentate neurons that can play diverse roles in hippocampal function. Understanding the physiological function of adult born neurons is an essential component of dissecting the significance and purpose of adult neurogenesis, a dramatic form of brain plasticity that may be a therapeutic target for numerous brain disorders.