CMA: Network plasticity in acquired epileptogenesis

CMA：获得性癫痫发生中的网络可塑性

• 批准号: 10341042
• 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/10341042
• 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; Disease; Electrophysiology (science); Epilepsy; Epileptogenesis; Excision; Fire - disasters; GABA Receptor; Goals; High Frequency Oscillation; Hippocampus (Brain); Image; Imaging Device; Impaired cognition; In Vitro; Injury; Interneurons; Intervention; Laboratories; Lead; Learning; Measures; Memory; Mental Depression; Microscope; Moods; 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; War; 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）是成年人中最常见的癫痫的形式，也是主要的残疾来源 退伍军人人口通常是由战时头部受伤引起的。超过1/3的TLE患者没有 对抗惊厥药的反应，许多不是癫痫手术的候选者。因此，新的 需要治疗以防止最初侮辱后癫痫的发展。然而，机制 在状态（SE）状态下直接导致癫痫发育（SE）仍然很差 理解。对这些机制的深刻而精确的理解对于开发干预措施至关重要 可以治疗时间癫痫，而无需药物的副作用和大型手术的潜在残疾 切除。为了确定SE之后最早的特定细胞类型的网络动态变化， 我们已经开发了一个微型显微镜，该显微镜与高通道完全集成 细胞外电生理记录装置（E-SCOPE）。我们假设超同步射击 白蛋白阳性（PV+）和生长抑素+（SOM+）中间神经元的参与度的逐渐减少 侮辱后的癫痫发作时期出现。我们还假设这些病理回路 兴奋性和抑制性神经元的动力学将在200-400 Hz高频期间很容易观察到 振荡（HFOS）已显示为高脱氧癫痫电路的生物标志物。在目标1中，我们将 测量在病理快速波纹和生理过程中PV+和SOM+神经元如何激活 锋利的波浪在癫痫发作期间涟漪。在AIM 2中，我们将测量空间编码的精度 通过兴奋性神经元以及在生理锋利波浪和合奏的重新激活 病理迅速在整个癫痫发作。此信息对于识别单元格至关重要 预防癫痫发生的干预措施的特定靶标。总体策略：我们的总体目标 协作功绩提案是确定海马和新皮层电路的关键变化 最初侮辱后促进癫痫和认知功能障碍的发展。其他建议的目的： 1。Wasterlain将使用包括EM免疫细胞化学在内的免疫细胞化学技术来量化变化 在突触的GABA受体表达中和突触间空间中。 2。Naylor将使用体外切片 贴片夹记录，光遗传学和计算建模，以了解功能连接如何 在此关键时期，不同的中间类型类型会发生变化。 3。Smirnakis将使用 电生理技术和体内介质两光子钙成像，以跟踪活性模式 在此期间，新皮质神经元的 驱动癫痫的发展。所有研究都是独立的，但彼此深入了解， 维度理解将是在这种高度复杂和残疾疾病中取得进展的关键。