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，每100人中就有1人患有癫痫 以反复发作的局灶性癫痫为特征。这些癫痫发作是由起源于 在内侧颞叶，最常见的是海马体结构。大脑皮层齿状回 慢性TLE患者海马区结构高度重组；与疾病相关的“齿状门”重构 被认为为同步放电和癫痫的传播开辟了病理传导通路 穿过内侧的颞叶。然而，这种病理生理学理解缺乏机械性。 大尺度同步动力学如何从齿状回的变化中出现的解释 微电路级。特别是，齿状回四个主要种群的集体活动是如何， 即成人出生和成熟的颗粒细胞、苔藓细胞和中间神经元，形成癫痫样网络水平。 事件仍未可知。这项建议旨在描述这些人群在发作间歇期的活动特征。 事件和发作，并检验宏观层面网络事件出现的理论模型 微观层次的系综的活动。 为了解决这个问题，我将同时使用活体双光子钙成像和局域场 行为学样小鼠在海马区海人酸样癫痫模型中的电位记录 慢性TLE小鼠齿状回基因识别群体的活动动态及其相关性 它们具有局域场势的宏观特征。在目标1中，我将在以下方面描述这四个群体的特征 发作间歇期、病理性发作间歇期和癫痫发作期间。最近的体外研究工作已经完成 研究表明，在发作间歇期，不同的齿状回神经元群被激发。在目标2中，我提出一个 大尺度癫痫样事件重新募集微回路的机制发生模型。这款车 预测发作间期事件期间的网络活动提供病理结构的一系列快照 这使得慢性癫痫网络能够支持癫痫发作。这里描述的实验和建模 将提供第一个活体表征的主要神经元群体的活动动力学 癫痫的齿状回，并有可能统一微观和宏观的疾病叙述。

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.