Inhibitory Neural Circuits in Dentate Function

海马齿状回通过改变密集的大脑皮质模式参与了海马区的记忆编码。 将感觉和空间信息转化为特定背景的稀疏神经表示。多样化的局部抑制 在这个过程中，电路是必不可少的，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的时间都是活跃的。齿状回也不断地产生新的神经元。 在整个生命过程中，通过经验依赖的结构为成人大脑的可塑性提供底物 新赛道。公认的是，GABA受体介导的机制严格调控细胞增殖和 成体神经元的功能整合。因此，GABA能中间神经元既提供了对 成熟的齿状神经元，并调节成年出生神经元的产生。这个项目的目标是 确定一种高度丰富的GABA能中间神经元亚型如何对抑制和 齿状回的神经发生功能。这个被称为常春藤/神经网状细胞(Ings)的中间神经元家族 由于无法使用遗传方法选择性地以它们为目标，因此相对被忽视。我们会 通过验证识别和操作ING的新工具并比较它们的功能来解决这一障碍 与高度研究的小白蛋白(PV)表达快速尖峰的中间神经元。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、内在和突触属性，这表明它们 在齿状突起抑制和神经发生中起着不同的作用。根据我们的初步数据，我们假设 慢峰Ings使用GABAA和GABAB受体激活来加强稀疏但高保真 刺激成熟的GC以及调节齿状神经发生的早期阶段。我们将结合蜂窝 并用光遗传学方法进行电路水平分析，以评估慢脉冲中间神经元在两者中的作用 抑制和神经发生。在了解了慢峰中间神经元亚型的细胞特性后， 我们将剖析它们在控制GC抑制和脉冲计时方面的作用，并与快速脉冲的结果进行比较 中间神经元。我们将使用光遗传沉默来确定各个神经元间对 齿状兴奋性，重点是GABAB介导的抑制以及慢峰和快峰之间的相互作用 子类型。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，以及 GABAB受体介导的抑制在年轻和成熟GC不同兴奋性中的作用。这个 这些研究的结果将为深入了解齿状体内慢峰中间神经元的功能提供基础资料。 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.