The Role of Inflammation in Post-stroke Epileptogenesis

炎症在中风后癫痫发生中的作用

• 批准号: 9899334
• 负责人: Jeanne T Paz
• 金额: $ 41.3万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899334
• 关键词: Anatomy; Animal Model; Animals; Anti-Inflammatory Agents; Back; Biological Markers; Biomedical Engineering; Blocking Antibodies; Brain; Brain Injuries; Cell physiology; Cerebral cortex; Child; Chronic; Complement; Complement 1q; Data; Development; Disease; Elderly; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Etiology; Genetic; Gliosis; Goals; Hot Spot; Immune; Impaired health; In Vitro; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injections; Injury; Lasers; Lead; Lesion; Link; Measures; Modeling; Molecular; Neuroglia; Neurosciences; Outcome; Pharmacology; Phase; Phenocopy; Prevention; Process; Proteins; Rattus; Recovery of Function; Research; Role; Seizures; Slice; Source; Status Epilepticus; Stroke; Synapses; System; Technology; Testing; Thalamic structure; Therapeutic; Time; Up-Regulation; Viral; Visual system structure; Work; astrogliosis; cytokine; disability; experimental study; in vivo; insight; neural circuit; novel; novel marker; optogenetics; patch clamp; post stroke; prevent; public health relevance; relating to nervous system; stroke model; synaptic inhibition; synaptic pruning; tool

 DESCRIPTION (provided by applicant): Epilepsy is a common consequence of brain insults, such as brain injuries, status epilepticus, and cerebrocortical stroke in the elderly and children. Despite ongoing research, there are no treatments that prevent epilepsy after brain insults. Each year, 15 million people worldwide suffer a stroke. Stroke is followed by a latent period (month to years) during which the brain goes through changes leading to the onset of chronic epilepsy. Understanding the maladaptive process so the development of epilepsy ("epileptogenesis") during the latent period can be prevented or treated is the holy grail of epilepsy research. Our preliminary data that form the basis of this proposal suggest that persistent inflammation involving glial cells may be a key component of epileptogenesis after stroke in rats. We previously found that cerebrocortical stroke leads to neural reorganization in the thalamocortical system and that the thalamus becomes hyperexcitable within the first week after stroke. Silencing the thalamic "hot spot" with optogenetic tools is sufficient to abort the epileptic seizures in real-time. We previously showed these hot spots to be causally involved in epileptic seizures (after the onset of chronic post-stroke epilepsy). They are associated with neural circuit plasticity co-localized with a permanent and focal astrogliosis and microgliosis and a massive upregulation of C1q, an immune molecule of the complement cascade, in the region that is causally involved in epileptic seizures. C1q is known for its role in synaptic pruning and circuit plasticity during normal development in the visual system, but our findings suggest that C1q may have a role in circuit plasticity after brain insults such as stroke. Our pilot data indicae that anti-inflammatory treatments that modify the gliosis also prevent the circuit hyperexcitabilit and deficits in synaptic inhibition and that selectively inducing gliosis via viral approaches phenocopies the deficits in synaptic inhibition and induces circuit hyperexcitability. We hypothesize that the glial-induced inflammation and C1q in the thalamus have key roles in the maladaptive cellular and circuit plasticity that leads from stroke to epilepsy. The goal of the proposed research is to determine the role of gliosis in epileptogenic circuit reorganization in th thalamocortical system. We will combine cellular physiology, systems neuroscience, and bioengineering to determine whether gliosis and/or blocking C1q actions after stroke will prevent epileptogenesis and whether disrupting the gliosis and blocking C1q actions during the chronic epileptic phase (i.e., after epilepsy has developed) will be sufficient to "go back in time" to modify the disease and cure epilepsy. This project may lead to novel biomarkers in epilepsy (thalamic gliosis and C1q) and novel treatments to prevent epilepsy after brain lesions, such as stroke.

 描述（由申请人提供）：癫痫是脑损伤的常见后果，例如老年人和儿童的脑损伤、癫痫持续状态和脑皮质中风。 尽管正在进行研究，但尚无治疗方法可以预防脑损伤后的癫痫。全世界每年有 1500 万人中风。中风之后是一段潜伏期（数月至数年），在此期间大脑会经历导致慢性癫痫发作的变化。了解适应不良过程，从而预防或治疗潜伏期癫痫的发展（“癫痫发生”）是癫痫研究的圣杯。 我们构成该提议基础的初步数据表明，涉及神经胶质细胞的持续炎症可能是大鼠中风后癫痫发生的关键组成部分。我们之前发现，脑皮质中风会导致丘脑皮质系统的神经重组，并且丘脑在中风后的第一周内变得过度兴奋。用光遗传学工具沉默丘脑“热点”足以实时中止癫痫发作。我们之前表明这些热点与癫痫发作（慢性中风后癫痫发作后）有因果关系。它们与神经回路可塑性相关，神经回路可塑性与永久性和局灶性星形胶质细胞增生和小胶质细胞增生共同定位， C1q（补体级联的一种免疫分子）在与癫痫发作有关的区域中大量上调。 C1q 以其在视觉系统正常发育过程中突触修剪和回路可塑性中的作用而闻名，但我们的研究结果表明，C1q 可能在中风等脑损伤后的回路可塑性中发挥作用。我们的试验数据表明，改变神经胶质增生的抗炎治疗还可以防止神经回路过度兴奋和突触抑制缺陷，并且通过病毒方法选择性诱导神经胶质增生可表型突触抑制缺陷并诱导神经回路过度兴奋。 我们假设丘脑中神经胶质诱导的炎症和 C1q 在导致中风和癫痫的细胞适应不良和回路可塑性中发挥关键作用。本研究的目的是确定神经胶质增生在丘脑皮质系统致癫痫回路重组中的作用。我们将结合细胞生理学、系统神经科学和生物工程来确定中风后神经胶质增生和/或阻断 C1q 作用是否会预防癫痫发生，以及在慢性癫痫期（即癫痫发生后）破坏神经胶质增生和阻断 C1q 作用是否足以“回到过去”以改变疾病并治愈癫痫。该项目可能会产生新的癫痫生物标志物（丘脑神经胶质增生和 C1q）以及预防中风等脑损伤后癫痫的新疗法。