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 岁以下人群的脑部疾病，表现为精神错乱、精神错乱和癫痫发作。 可能需要药物诱导昏迷 抗 NMDAR 最令人衰弱的并发症。 脑炎是一种永久性认知障碍，在脑成像或大脑成像没有结构变化的情况下发生 组织损失的组织病理学证据；记忆脑病的病理生理学仍不清楚。 困难导致康复患者的生活质量下降；因此，确定潜在的机制； 自身免疫性脑炎中认知功能的丧失将有助于制定减轻和缓解认知功能的策略 来自动物研究的新文献表明，这些缺陷的逆转。 在长时间的化学诱导过程中，海马中的成体神经源性干细胞（NSC）减少 阿尔茨海默病模型中的癫痫发作和自发性癫痫发作，以及神经发生的破坏 此外，癫痫发作的减弱导致神经发生的恢复和记忆力的下降。 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 在抗 NMDAR 抗体被动转移过程中出现癫痫发作和记忆障碍 此外，我们还发现脑炎中的海马炎症会导致脑炎的发生。 记忆缺陷；然而，神经发生在认知缺陷发展中的作用尚未得到证实。 该应用程序的目的是结合组织学、成像和行为数据来确定。 自身免疫性癫痫发作和炎症如何影响抗 NMDAR 中海马 NSC 的增殖 我们的首要目标是量化持续暴露于脑炎期间 NSC 库中的细胞特异性变化。 使用神经祖细胞的免疫组织化学表型标记在我们的小鼠模型中检测抗 NMDAR 抗体 然后我们将可视化并量化细胞和体视学分析（目标 1a）。 使用 3'-脱氧-3'-[18F] 氟-体内正电子发射断层扫描 (PET) 成像的海马 NSC 库 L-胸苷（目标 1b）并使用海马特异性行为评估相应的记忆变化 测试（目标 1c）在第二只手臂下，我们将可视化海马体的区域炎症模式。 使用放射性标记易位蛋白 (TSPO)-PET 并确定异常程度 大脑成像与小鼠的记忆和学习功能相关（目标 2a）。 旨在减轻自身免疫性脑炎认知丧失的新治疗策略，我们将确定是否 阿那白滞素（anakinra）是一种白细胞介素 1 受体拮抗剂，之前已被证明可以减少海马 炎症并恢复小鼠的记忆，还可以逆转癫痫发作中的异常神经发生（目标 2b）。 该项目的成功完成将解决理解细胞机制的一个关键差距 自身免疫性脑炎的慢性记忆丧失，并将导致新的有针对性的干预措施的发现。