Newborn Neurons in the Adult Hippocampal Network

描述(申请人提供)：成年神经发生持续存在于哺乳动物的齿状回。神经产生受到大量病理条件的干扰，越来越多的人意识到，疾病模型中神经发生的中断可能会导致认知和情感功能障碍。尽管在啮齿动物疾病模型中成年神经发生的损害被高度证实，但关于成年出生的神经元如何在细胞和电路水平上对正常和异常的海马体功能起作用的了解较少。目前尚不清楚，如此少量的神经元--估计只占年轻人颗粒细胞总数的1-3%-如何会对行为产生相当大和不同的影响。大多数理论认为，神经发生产生一个不断更新的未成熟颗粒细胞群，这些未成熟颗粒细胞具有与先前存在的细胞不同的功能，并将相当多的注意力集中在其内在的超兴奋性上。令人惊讶的是，不同突触的潜在作用 成体出生的颗粒细胞的连接性还没有得到充分的研究。我们的长期目标是了解未成熟颗粒细胞的生理特征如何对它们的功能做出贡献。该项目的目标是确定成熟过程中突触连接的差异如何影响颗粒细胞招募，从而潜在地允许未成熟和成熟细胞处理网络活动的不同组成部分。根据我们的初步数据，我们假设，与成熟颗粒细胞相比，来自皮质和海马区的不同神经来源的神经支配导致海马内网络活动对未成熟颗粒细胞的招募更多。我们将使用体外切片生理学和各种转基因小鼠模型和光遗传学来解决这一假说。首先，我们将比较颗粒细胞在发育过程中的神经支配，以测试未成熟颗粒细胞具有较高的皮质输入特异性，与较低水平的皮质神经支配相对应，这限制了它们对皮质活动的反应。其次，我们将确定苔藓细胞活动如何有助于颗粒细胞在成熟过程中尖峰。苔藓细胞是门内的谷氨酸能神经元，主要通过长距离投射向颗粒细胞层提供反馈兴奋。苔藓细胞的激活通常通过双突触抑制产生对成熟颗粒细胞的抑制，而未成熟颗粒细胞的突触连接表明兴奋占主导地位。苔藓细胞对颗粒细胞突触整合的控制知之甚少，因此这些实验的结果将为这一重要但经常被忽视的海马区电路提供新的信息。最后，我们将使用成像和活体方法研究肺门苔藓细胞活动对颗粒细胞群活动的贡献。总之，这些研究结果将为了解不同的突触连接如何有助于激活未成熟的GCs，从而控制它们参与DG网络活动提供了基本的见解。这些结果将为成人神经发生的功能提供新的见解，这是一种戏剧性的脑部可塑性形式，已成为许多病理疾病的治疗靶点。

DESCRIPTION (provided by applicant): Adult neurogenesis persists in the dentate gyrus of mammals. Neural production is perturbed by a large number of pathological conditions, and there is a growing realization that disrupted neurogenesis in disease models can contribute to cognitive and emotive dysfunction. Despite the highly documented impairments of adult neurogenesis in rodent disease models, less is known about how adult-born neurons contribute to normal and abnormal hippocampal function at the cellular and circuit level. It is unclear how such a small number of neurons, estimated to be 1-3% of the total population of granule cells in young adults, could have sizable and varied consequences for behavior. Most theories implement the idea that neurogenesis produces a continually renewing population of immature granule cells that have distinct functions from pre-existing cells, with considerable attention focused on their intrinsic hyperexcitability. Surprisingly, the potential role of distinct synaptic connectivity of adult-born granule cells has not been fully explored. Our long-term goal is to understand how the physiological characteristics of immature granule cells contribute to their function. The goal of this project is to determine how differences in synaptic connectivity across maturation affect granule cell recruitment, potentially allowing immature and mature cells to process distinct components of network activity. Based on our preliminary data, we hypothesize that distinct innervation from cortical and hippocampal sources results in greater recruitment of immature granule cells by intra-hippocampal network activity compared to mature granule cells. We will use in vitro slice physiology and a variety of transgenic mouse models and optogenetics to address this hypothesis. First, we will compare innervation of granule cells across their development to test the idea that immature granule cells have high cortical input specificity, corresponding to low levels of cortical innervation, that limits their responsiveness to cortical activity. Second, we will determine how mossy cell activity contributes to granule cell spiking across maturation. Mossy cells are glutamatergic neurons within the hilus that provide feedback excitation to the granule cell layer via predominately long-range projections. Whereas mossy cell activation typically generates inhibition of mature granule cells via di-synaptic inhibition, he synaptic connectivity of immature granule cells suggests that excitation predominates. Little is known about mossy cell control of granule cell synaptic integration, thus the results of these experiments will provide novel information about this important but often neglected hippocampal circuit. Finally, we will examine how hilar mossy cell activity contributes to granule cell population activity using imaging and in vivo approaches. Together the results of these studies will provide fundamental insight into how distinct synaptic connectivity contributes to the activation of immature GCs and thus controls their participation in DG network activity. These results will provide novel insight into the function of adult neurogenesis, a dramatic form of brai plasticity that has become a therapeutic target for numerous pathological conditions.