CMA: Network plasticity in acquired epileptogenesis

CMA：获得性癫痫发生中的网络可塑性

• 批准号: 10553128
• 负责人: Peyman Golshani
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553128
• 关键词: Adult; Affect; Animals; Anticonvulsants; Biological Markers; Brain; Calcium; Cell Death; Cells; Chronic; Code; Cognitive; Cognitive deficits; Communication; Complex; Computer Models; Craniocerebral Trauma; D Cells; Development; Devices; Dimensions; Disease; Disinhibition; Electrophysiology (science); Epilepsy; Epileptogenesis; Excision; Fire - disasters; GABA Receptor; Goals; High Frequency Oscillation; Hippocampus; Image; Imaging Device; Impaired cognition; In Vitro; Injury; Interneurons; Intervention; Laboratories; Learning; Measures; Memory; Mental Depression; Microscope; Moods; Neocortex; Neurons; Operative Surgical Procedures; Parvalbumins; Pathologic; Patients; Pattern; Pharmaceutical Preparations; Physiological; Pilocarpine; Population; Recurrence; Seizures; Slice; Somatostatin; Source; Status Epilepticus; Synapses; Techniques; Temporal Lobe Epilepsy; Time; Veterans; axonal sprouting; cell type; comorbidity; disability; excitatory neuron; extracellular; hippocampal pyramidal neuron; immunocytochemistry; in vivo; inhibitory neuron; military veteran; miniaturize; neocortical; neural circuit; open source tool; optogenetics; patch clamp; place fields; prevent; receptor expression; recruit; side effect; therapy development; tool; two-photon

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and a major source of disability in the veteran population as it is frequently caused by war-time head injuries. More than 1/3 of TLE patients do not respond to anticonvulsant medications and many are not candidates for epilepsy surgery. Therefore, new treatments are needed to prevent the development of epilepsy after the initial insult. Yet, the mechanisms that lead to the development of epilepsy during the period directly after status epilepticus (SE) are still poorly understood. A deep and precise understanding of these mechanisms is critical for development of interventions that can treat temporal epilepsy without the side-effects of medications and potential disability from large surgical resections. To determine the network dynamic changes in specific cell types during the earliest period after SE, we have developed a miniaturized microscope that is completely integrated with a high channel extracellular electrophysiology recording device (E-Scope). We hypothesize that hypersynchronous firing of parvalbumin positive (PV+) and progressive decreased engagement of somatostatin+ (SOM+) interneurons emerge during the epileptogenic period after the insult. We also hypothesize that these pathological circuit dynamics in both excitatory and inhibitory neurons will be readily observed during 200-400 Hz high frequency oscillations (HFOs) have been shown to be a biomarker for hyper-excitable epileptic circuit. In Aim 1 we will measure how PV+ and SOM+ neurons become activated during pathological fast ripples and physiological sharp-wave ripples through the epileptogenic period. In Aim 2, we will measure the precision of spatial coding by excitatory neurons and the reactivation of ensembles during physiological sharp-wave ripples and pathological fast ripples through the epileptogenic period. This information will be critical for identifying the cell specific targets for interventions to prevent epileptogenesis. Overall Strategy: The overall goal of our collaborative merit proposal is to determine the key changes in hippocampal and neocortical circuitry that promotes the development of epilepsy and cognitive dysfunction after the initial insult. Aims of Other Proposals: 1. Wasterlain will use immunocytochemical techniques, including EM immunocytochemistry, to quantify changes in the GABA receptor expression at the synapse and in the peri-synaptic space. 2. Naylor will use in-vitro slice patch clamp recordings, optogenetics, and computational modeling to understand how the functional connectivity of different interneuron types changes during this key period. 3. Smirnakis will use a combination of electrophysiological techniques and in-vivo mesoscopic two-photon calcium imaging to track the activity patterns of neocortical neurons during this period, to understand how hippocampal-cortical communication changes and drives the development of epilepsy. All studies are independent, yet deeply inform each other, as a multi- dimensional understanding will be key for making progress in this highly complex and disabling disorder.

颞叶癫痫 (TLE) 是成人最常见的癫痫形式，也是成人残疾的主要根源。 退伍军人群体，因为它经常因战时头部受伤而造成。超过 1/3 的 TLE 患者没有 对抗惊厥药物有反应，许多人不适合进行癫痫手术。因此，新 初次损伤后需要进行治疗以预防癫痫的发展。然而，这些机制 导致癫痫持续状态（SE）后立即发生癫痫的情况仍然很差 明白了。对这些机制的深入而准确的理解对于干预措施的制定至关重要 可以治疗颞叶癫痫，没有药物副作用和大型手术带来的潜在残疾 切除术。为了确定SE后最早时期特定小区类型的网络动态变化， 我们开发了一款与高通道完全集成的微型显微镜 细胞外电生理记录装置（E-Scope）。我们假设超同步触发 小白蛋白阳性 (PV+) 和生长抑素+ (SOM+) 中间神经元的参与逐渐减少 出现在损伤后的致痫期。我们还假设这些病理回路 在 200-400 Hz 高频期间，很容易观察到兴奋性和抑制性神经元的动态变化 振荡（HFO）已被证明是高兴奋性癫痫回路的生物标志物。在目标 1 中，我们将 测量 PV+ 和 SOM+ 神经元在病理性快速波动和生理性快速波动期间如何被激活 尖波在癫痫发作期产生涟漪。在目标 2 中，我们将测量空间编码的精度 通过兴奋性神经元和生理尖波涟漪期间群的重新激活和 病理性快速波动贯穿整个癫痫发作期。该信息对于识别细胞至关重要 预防癫痫发生的干预措施的具体目标。总体战略：我们的总体目标 协作优点提案的目的是确定海马和新皮质回路的关键变化 在初次损伤后促进癫痫和认知功能障碍的发展。其他提案的目的： 1. Wasterlain 将使用免疫细胞化学技术，包括 EM 免疫细胞化学，来量化变化 突触和突触周围空间的 GABA 受体表达。 2. Naylor将使用体外切片 膜片钳记录、光遗传学和计算模型，以了解功能连接如何 在此关键时期，不同中间神经元类型的变化。 3. Smirnakis 将结合使用 电生理技术和体内介观双光子钙成像来跟踪活动模式 在此期间的新皮质神经元的研究，以了解海马-皮质通讯如何变化和 促进癫痫的发展。所有的研究都是独立的，但作为一个多学科的研究，彼此之间有着深入的了解。 维度理解将是在这种高度复杂和致残的疾病方面取得进展的关键。