Dissecting microcircuit alterations in the epileptic dentate gyrus with functional imaging

颞叶癫痫（TLE）是一种常见的神经系统疾病，影响高达1/100的人， 以反复的局灶性癫痫发作为特征。这些癫痫发作是由同步神经元活动驱动的， 颞叶内侧最常见的是海马结构大脑齿状回区 慢性颞叶癫痫患者海马结构高度重组;与疾病相关的“齿状门”重塑 被认为打开了同步放电和癫痫传播的病理传导通路 穿过内侧颞叶然而，这种病理生理学的理解缺乏一种机制， 解释如何宏观同步动力学出现的变化，齿状回在 微电路级特别是，齿状回的四个主要群体的集体活动， 也就是说，成年和成熟的颗粒细胞，苔藓细胞和中间神经元，引起癫痫样网络水平 事件仍然未知。该建议旨在描述这些人群在发作间期的活动特征 事件和癫痫发作，并从宏观上检验了网络事件出现的理论模型 微观层次的整体活动。 为了解决这个问题，我将使用同时在体内双光子钙成像和局部场 在海马内海人酸癫痫模型中的行为小鼠中的电位记录 慢性TLE小鼠齿状回中遗传鉴定群体的活动动力学， 它们具有局部场势的宏观特征。在目标1中，我将描述这四个群体的特征， 发作间期、病理性发作间期事件期间和癫痫发作期间。最近的体外研究工作 显示了在发作间期事件中齿状回神经元的不同集合。在目标2中，我提出了一个 通过宏观癫痫样事件招募微电路的机械生成模型。该模型 预测发作间期的网络活动提供了一系列病理结构的快照 让慢性癫痫网络支持癫痫发作。这里描述的实验和建模 将提供第一个在体内表征的主要神经元群体的活动动力学， 癫痫齿状回，并有可能统一微观和宏观的叙述疾病。

Temporal lobe epilepsy (TLE) is a common neurological disorder affecting up to 1 in 100 people and characterized by recurrent focal seizures. These seizures are driven by synchronous neuronal activity originating in the mesial temporal lobe, most commonly the hippocampal formation. The dentate gyrus region of the hippocampal formation is highly reorganized in chronic TLE; disease-associated remodeling of the “dentate gate” is thought to open up pathological conduction pathways for synchronous discharges and seizures to propagate through the mesial temporal lobe. However, this pathophysiological understanding lacks a mechanistic explanation of how macroscale synchronous dynamics emerge from alterations of the dentate gyrus at the microcircuit level. In particular, how the collective activity of the four principal populations of the dentate gyrus, i.e., adult-born and mature granule cells, mossy cells, and interneurons, gives rise to epileptiform network-level events remains unknown. This proposal aims to characterize the activity of these populations during interictal events and seizures, and test a theoretical model of the emergence of macrolevel network events from the activity of microlevel ensembles. To address this question, I will use simultaneous in vivo two-photon calcium imaging and local field potential recordings in behaving mice in the intrahippocampal kainic acid model of epilepsy to optically record activity dynamics of genetically identified populations in the dentate gyrus in mice with chronic TLE, and correlate them with macrolevel features of the local field potential. In Aim 1, I will characterize these four populations in the interictal period, during pathological interictal events, and during seizures. Recent work in vitro work has shown that distinct ensembles of dentate gyrus neurons fire during interictal events. In Aim 2, I propose a mechanistic generative model for the recruitment of microcircuits by macroscale epileptiform events. This model predicts that network activity during interictal events provides a series of snapshots of the pathological structure that allows the chronically epileptic network to support seizures. The experiments and modeling described here will provide the first in vivo characterization of activity dynamics of the principal neuronal populations of the epileptic dentate gyrus, and have the potential to unify microscopic and macroscopic narratives of the disease.