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性脑炎的主要原因。 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 可能需要药物诱导昏迷抗NMDAR最令人衰弱的并发症 脑炎是一种永久性的认知障碍，发生在大脑成像没有结构变化的情况下， 组织损失的组织病理学证据;脑病的病理生理学仍不清楚。存储器 困难导致恢复期患者的生活质量差;因此， 自身免疫性脑炎中认知功能的丧失将允许开发减毒策略， 扭转这些赤字。来自动物研究的新兴文献表明， 海马中的成体神经源性干细胞（NSC）在长时间的化学诱导过程中减少， 癫痫发作和自发性癫痫发作在阿尔茨海默病模型中， 与记忆衰退同时发生。此外，癫痫发作的减弱导致神经发生的恢复， 逆转记忆缺陷。我们开发了一种自身免疫性癫痫发作的小鼠模型， 在抗NMDAR抗体被动转移期间发生癫痫发作和记忆障碍， 患者此外，我们发现脑炎中的海马炎症有助于脑缺血的发展。 记忆缺陷;然而，神经发生在认知缺陷发展中的作用还没有被证实。 探讨了该应用程序的目的是联合收割机结合组织学、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海马神经干细胞的增殖 脑炎我们的第一个目标是量化持续暴露于NSC期间NSC池中细胞特异性的变化。 在我们的小鼠模型中使用神经祖细胞的免疫组织化学表型标记物的抗NMDAR抗体 细胞和体视学分析（目标1a）。然后，我们将可视化和量化的时间变化， 使用3 '-脱氧-3'-[18F]氟- L-胸苷（Aim 1b），并使用海马特异性行为检测评估相应的记忆变化。 测试（目标1c）。在第二只手臂下，我们将观察海马体区域炎症的模式 使用放射性标记的转运蛋白（TSPO）-PET，并确定异常的程度， 脑成像与小鼠的记忆和学习功能有关（目的2a）。目标是开发 新的治疗策略旨在减轻自身免疫性脑炎的认知丧失，我们将确定是否 阿那白滞素是一种白细胞介素-1受体拮抗剂， 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（目的2b）。这 该项目的成功完成将解决理解细胞机制的关键差距， 自身免疫性脑炎的慢性记忆丧失，并将导致新的靶向干预措施的发现。