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: 10494053
• 负责人: Olga Taraschenko
• 金额: $ 19.18万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10494053
• 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; Thymidine; Tissues; anakinra; antagonist; 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岁以下人群的脑部疾病。它表现为精神错乱、精神错乱和癫痫发作 这可能需要药物诱导的昏迷。抗NMDAR最令人衰弱的并发症 脑炎是一种永久性的认知功能衰竭，在没有脑部成像或脑部结构改变的情况下发生 组织丢失的组织病理学证据；脑病的病理生理学仍不清楚。记忆 困难导致康复患者的生活质量较差；因此，确定潜在的机制 自身免疫性脑炎认知功能的丧失将允许制定衰减和治疗的策略 扭转这些赤字。来自动物研究的新兴文献表明，正常的增殖 成年神经源性干细胞(NSC)在长时间的化学诱导过程中会减少 阿尔茨海默病模型中的癫痫发作和自发性癫痫发作以及神经发生的中断 伴随着记忆力的衰退。此外，癫痫发作的减轻导致神经再生的恢复和 逆转记忆缺陷。我们开发了一种自身免疫性癫痫的小鼠模型，并表明 在被动转移抗NMDAR抗体过程中出现癫痫发作和记忆障碍 病人。此外，我们还发现，脑炎时的海马区炎症参与了脑炎的发生。 记忆缺陷；然而，神经发生在认知缺陷发展中的作用尚未被 探索过了。这个应用程序的目的是结合组织学、成像和行为数据来确定 自身免疫性惊厥和炎症在抗NMDAR中对海马神经干细胞增殖的影响 脑炎。我们的第一个目标是量化持续暴露在神经干细胞池中的细胞特异性变化 用神经前体细胞免疫组织化学表型标记物检测小鼠模型中的抗NMDAR抗体 细胞和体视学分析(目标1a)。然后，我们将可视化并量化 3‘-脱氧-3’-[18F]荧光素在体正电子发射断层扫描中的应用 L-胸腺嘧啶核苷(Aim 1b)，并用海马特异性行为评估相应的记忆变化 测试(目标1c)。在第二个手臂下，我们将可视化海马体中的局部炎症模式 使用放射性标记转运蛋白(TSPO)-PET并确定异常程度如何 脑成像与小鼠的记忆和学习功能有关(目标2a)。以发展为目标 旨在减轻自身免疫性脑炎认知障碍的新治疗策略，我们将确定是否 给予白介素1受体拮抗剂Anakinra可减少海马区 炎症和恢复小鼠的记忆，也逆转癫痫发作中的异常神经发生(目标2b)。这 该项目的成功完成将解决在理解细胞机制方面的一个关键空白。 自身免疫性脑炎的慢性记忆丧失，将导致新的靶向干预措施的发现。