The role of hippocampal neurogenesis in the development of cognitive deficits in autoimmune encephalitis with seizures

海马神经发生在自身免疫性脑炎癫痫发作认知缺陷发展中的作用

• 批准号: 10429050
• 负责人: Olga Taraschenko
• 金额: $ 26.81万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-14 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10429050
• 关键词: Address; Adult; Affect; Age-Years; Aging; Alzheimer' s disease model; Animals; Attenuated; Autoimmune; Autoimmune encephalitis; Behavioral; Brain Diseases; Brain imaging; Cells; Chemicals; Chronic; Cognitive; Cognitive deficits; Coma; Complication; Confusion; Data; Development; Encephalitis; Encephalopathies; Exposure to; Failure; Fc Receptor; Functional disorder; Goals; Hippocampus (Brain); Impaired cognition; Inflammation; Inflammatory; Intervention; Learning; Literature; Memory; Memory Loss; Memory impairment; Mus; N-Methyl-D-Aspartate Receptors; Patients; Pattern; Persons; Pharmacology; Positron-Emission Tomography; Proteins; Psychoses; Quality of life; Radiolabeled; Role; Seizures; Structure; Thymidine; Tissues; anakinra; arm; attenuation; behavior test; cognitive development; cognitive function; cognitive neuroscience; histological image; in vivo; mouse model; nerve stem cell; neurogenesis; novel therapeutic intervention; phenotypic biomarker; receptor; restoration; stem cells

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the leading cause of noninfectious inflammatory brain disorders in persons younger than 30 years of age. It manifests with confusion, psychosis, and seizures that may require pharmacologically-induced coma. The most debilitating complication of anti-NMDAR encephalitis is permanent cognitive failure that occurs in the absence of structural changes on brain imaging or histopathological evidence of tissue loss; the pathophysiology of encephalopathy remains unclear. Memory difficulties contribute to poor quality of life in recovering patients; therefore, identifying mechanisms underlying the loss of cognitive function in autoimmune encephalitis will allow to develop strategies for attenuation and reversal of these deficits. Emerging literature from animal studies has demonstrated that normal proliferation of the adult neurogenic stem cells (NSC) in the hippocampus is reduced during prolonged chemically-induced seizures and spontaneous seizures in Alzheimer’s disease models, and the disruption of neurogenesis occurs in parallel with memory decline. Further, attenuation of seizures resulted in restoration of neurogenesis and reversal of memory deficits. We developed a mouse model of autoimmune seizures and showed that mice develop seizures and memory disturbances during the passive transfer of anti-NMDAR antibodies from patients. Further, we showed that hippocampal inflammation in encephalitis contributes to the development of memory deficits; however, the role of neurogenesis in the development of cognitive deficits has not been explored. This application’s aims are to combine the histological, imaging, and behavioral data to determine how autoimmune seizures and inflammation affect the proliferation of the hippocampal NSCs in anti-NMDAR encephalitis. Our first aim is to quantify the cell-specific changes in NSC pool during the sustained exposure to anti-NMDAR antibodies in our mouse model using immunohistochemical phenotypic markers of neuroprogenitor cells and stereological analyses (Aim 1a). We will then visualize and quantify the temporal changes in the hippocampal NSC pool using in vivo positron emission tomography (PET) imaging with 3’-deoxy-3’-[18F] fluoro- L-thymidine (Aim 1b) and assess the corresponding memory changes using hippocampal-specific behavioral tests (Aim 1c). Under the second arm, we will visualize the patterns of regional inflammation in the hippocampus using radiolabeled translocator protein (TSPO)-PET and establish how the extent of the abnormalities on the brain imaging relates to the memory and learning functions in mice (Aim 2a). With the goal of developing new therapeutic strategies aimed to attenuate cognitive loss in autoimmune encephalitis, we will determine if administration of anakinra, an interleulkin-1 receptor antagonist previously shown to decrease hippocampal inflammation and restore memory in mice, also reverses an aberrant neurogenesis in seizures (Aim 2b). This successful completion of the project will address a critical gap in understanding the cellular mechanisms of chronic memory loss in autoimmune encephalitis and will lead to the discovery of new targeted interventions.

抗N-甲基-D-天冬氨酸受体（NMDAR）脑炎是非感染性炎症的主要原因 30岁以下的患者脑疾病。它表现出混乱，精神病和癫痫发作 这可能需要药物引起的昏迷。抗NMDAR最令人衰弱的并发症 脑炎是在没有脑成像的结构变化的情况下发生的永久认知衰竭或 组织丧失的组织病理学证据；脑病的病理生理尚不清楚。记忆 困难导致康复患者的生活质量差；因此，确定基本机制 自身免疫性脑炎中认知功能的丧失将允许制定衰减和 这些缺陷的逆转。动物研究的新兴文献表明， 在化学诱导的延长期间，海马中的成年神经源性干细胞（NSC）降低 阿尔茨海默氏病模型中的癫痫发作和发作性癫痫发作以及神经发生的破坏发生 与记忆下降并联。此外，癫痫发作的衰减导致神经发生和 内存不足的逆转。我们开发了一种自身免疫性癫痫发作的小鼠模型，并表明小鼠 在反-NMDAR抗体的被动转移期间，会产生癫痫发作和记忆障碍 患者。此外，我们表明，脑炎的海马炎症有助于发展 内存定义；但是，神经发生在认知定义的发展中的作用并不是 探索。此应用程序的目的是结合组织学，成像和行为数据以确定 自身免疫性癫痫发作和炎症如何影响抗NMDAR中海马NSC的增殖 脑炎。我们的第一个目的是量化持续暴露期间NSC池的细胞特异性变化 我们的小鼠模型中使用神经元基因的免疫组织化学表型标记物中的抗NMDAR抗体 细胞和立体分析（AIM 1A）。然后，我们将可视化并量化 使用体内正电子发射断层扫描（PET）成像的海马NSC池与3'-脱氧-3' - [18F]氟 - L-胸腺苷（AIM 1B），并使用海马特异性行为评估相应的内存变化 测试（AIM 1C）。在第二臂下，我们将可视化海马中区域炎症的模式 使用放射性标记的转运蛋白（TSPO）-PET，并确定异常程度如何 大脑成像与小鼠记忆和学习功能的关系（AIM 2A）。以发展的目标 旨在减弱自身免疫性脑炎的认知损失的新理论策略，我们将确定是否确定 阿纳基拉（Anakinra 小鼠的炎症和恢复记忆也逆转了癫痫发作的异常神经发生（AIM 2B）。 成功完成该项目将解决了解细胞机制的关键差距 自身免疫性脑炎的慢性记忆力丧失，并将导致发现新的靶向干预措施。