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: 10597991
• 负责人: Olga Taraschenko
• 金额: $ 17.39万
• 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/10597991
• 关键词: 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; Histologic; Image; Impaired cognition; Inflammation; Inflammatory; Intervention; Learning; Literature; Memory; Memory Loss; Memory impairment; Mus; N-Methyl-D-Aspartate Receptors; Patients; Pattern; Persons; Positron-Emission Tomography; Proliferating; Proteins; Psychoses; Quality of life; Radiolabeled; Role; Seizures; Thymidine; Tissues; Visualization; anakinra; antagonist; arm; attenuation; behavior test; cognitive function; cognitive neuroscience; in vivo; mouse model; nerve stem cell; neurogenesis; novel therapeutic intervention; pharmacologic; 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