Inhibitory Neural Circuits in Dentate Function

齿状回通过转换致密的皮质模式， 感官和空间信息转化为特定情境的稀疏神经表征。不同的局部抑制 电路是必不可少的这一过程，维持低水平的神经活动，其中只有一小部分， 主神经元在任何给定时间都是活跃的。齿状回也不断产生新的神经元 在整个生命过程中，通过经验依赖性的结构， 新电路已经确定，GABA受体介导的机制严格调节增殖， 成年神经元的功能整合。因此，GABA能中间神经元提供了抑制性控制， 成熟的齿状神经元和调节成人出生的神经元的生产。该项目的目标是 确定高度丰富的GABA能中间神经元亚型如何有助于抑制和 齿状回的神经功能这种称为Ivy/神经胶质样细胞（INGs）的中间神经元家族具有 由于无法使用遗传方法选择性地靶向它们，因此相对被忽视。我们将 通过验证识别和操纵ING的新工具并比较它们的功能，来解决这一障碍 与高度研究的表达小清蛋白（PV）的快速尖峰中间神经元。这些快速和缓慢的扣球 中间神经元亚型具有高度不同的解剖，内在和突触特性，这表明它们 在齿状回抑制和神经发生中发挥独特的作用。根据我们的初步数据，我们假设， 缓慢尖峰ING使用GABAA和GABAB受体激活来执行稀疏但高保真 以及调节齿状神经发生早期阶段。我们将联合收割机 和电路水平的分析与光遗传学的方法来评估的作用，缓慢尖峰中间神经元在这两个 抑制和神经发生。在了解了慢尖峰中间神经元亚型的细胞特性之后， 我们将剖析它们在控制GC抑制和尖峰时间方面的作用，并与快速尖峰的结果进行比较， 中间神经元。我们将使用光遗传学沉默来确定相应的中间神经元对细胞凋亡的贡献。 齿状兴奋性，重点是GABAB介导的抑制和慢峰和快峰之间的相互作用 亚型最后，我们将测试慢尖峰中间神经元在干细胞增殖中的作用， GABAB受体介导的抑制在年轻和成熟GC的不同兴奋性中的作用。的 这些研究结果将为深入了解齿状回慢发放中间神经元的功能提供基础。 兴奋性和神经发生。

The dentate gyrus contributes to hippocampal memory encoding by transforming dense cortical patterns of sensory and spatial information into sparse neural representations of specific contexts. Diverse local inhibitory circuits are essential for this process, maintaining low levels of neural activity wherein only small fractions of principal neurons are active at any given time. The dentate gyrus also continually generates new neurons throughout life, providing a substrate for adult brain plasticity through experience-dependent construction of new circuits. It is well established that GABA receptor-mediated mechanisms tightly regulate proliferation and functional integration of adult-born neurons. Thus, GABAergic interneurons provide both inhibitory control of mature dentate neurons and regulate the production of adult-born neurons. The goal of this project is to determine how a highly abundant subtype of GABAergic interneuron contributes to both inhibitory and neurogenic functions in the dentate gyrus. This family of interneurons called Ivy/Neurogliaform cells (INGs) has been relatively neglected due to the inability to selectively target them using genetic approaches. We will address this roadblock by validating new tools to identify and manipulate INGs, and compare their functions with the highly-studied parvalbumin (PV)- expressing fast-spiking interneurons. These fast and slow-spiking interneuron subtypes have highly divergent anatomical, intrinsic and synaptic properties, suggesting that they play distinct roles in dentate inhibition and neurogenesis. Based on our preliminary data, we hypothesize that slow-spiking INGs use GABAA and GABAB receptor activation to enforce sparse yet high-fidelity spiking of mature GCs as well as regulate early stages of dentate neurogenesis. We will combine cellular and circuit level analysis with optogenetic approaches to assess the role of slow spiking interneurons in both inhibition and neurogenesis. After understanding the cellular properties of slow-spiking interneurons subtypes, we will dissect their role in controlling GC inhibition and spike timing, comparing with results from fast-spiking interneurons. We will use optogenetic silencing to determine the respective interneuron contributions to dentate excitability with a focus on GABAB mediated-inhibition and interactions between slow and fast-spiking subtypes. Finally, we will test the role of slow-spiking interneurons in stem cell proliferation, and the contribution of GABAB receptor-mediating inhibition in differential excitability of young and mature GCs. The results of these studies will provide fundamental insight into the function of slow-spiking interneurons in dentate excitability and neurogenesis.