From Defective Microglia to Cortical Activity and Pathological Behavior

从有缺陷的小胶质细胞到皮质活动和病理行为

• 批准号: 8645751
• 负责人: MARIO R CAPECCHI
• 金额: $ 40.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645751
• 关键词: A Mouse; Ablation; Affect; Alzheimer' s Disease; Attention; Autistic Disorder; Behavior; Behavioral; Biology; Bipolar Disorder; Birth; Bone Marrow; Bone Marrow Ablation; Bone Marrow Transplantation; Brain; Cell Lineage; Cells; Cerebrum; Complementary DNA; Complex; Diphtheria Toxin; Disease; Drug Prescriptions; Embryonic Development; Etiology; Exhibits; Filopodia; Freezing; Functional disorder; Ganciclovir; Gene Expression; Gene Expression Profile; Genes; Genetic; Grooming; Hair Removal; Hematopoietic; Herpesviridae; Human; ITGAM gene; Image; Immune System Diseases; Immune System and Related Disorders; Immune system; Infusion procedures; Label; Lasers; Lesion; Light; Link; Major Depressive Disorder; Mammals; Measures; Mental disorders; Microglia; Modification; Molecular; Mus; Mutant Strains Mice; Mutation; Neuroglia; Neurons; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Outcomes Research; Paper; Pathology; Peripheral; Photons; Population; Positioning Attribute; Procedures; Process; Property; Proteins; Publishing; Reporter; Rest; Risk; Role; Schizophrenia; Signal Transduction; Site; Source; Stem cells; Surface; Synapses; Synaptic Transmission; System; TK Gene; Tamoxifen; Technology; Testing; Trichotillomania; Vascularization; base; behavior influence; behavior test; chemokine; cohort; cytokine; diphtheria toxin receptor; genome wide association study; granulocyte; insight; loss of function; molecular marker; monocyte; mutant; neural circuit; neurophysiology; neuropsychiatry; optogenetics; research study; response; selective expression; tool; two-photon

DESCRIPTION (provided by applicant): Immunological dysfunction have been widely linked to many neuropsychiatric disorders including obsessive compulsive disorder (OCD), major depression, bipolar disorder, autism, schizophrenia and Alzheimer disease. In addition, results from genome wide association studies suggest that genes whose dysfunction have been implicated in immune dysfunction and/or signaling, contribute to increased risk to the above-mentioned mental disorders. However the basis for the above associations is not clear, which is cause or effect? Do the drugs prescribed for neuropsychiatric disorders affect the immune system? We have identified a mouse where defective microglia, the immune system of the brain, appears causal for a distinct pathological behavior. Further, a bone marrow transplant cures this mouse of its pathological behavior. In this mouse we have directly linked a deficiency in the immune system with pathological behavior. Mice with a mutation in Hoxb8 show unexpected behavior manifested by compulsive grooming and hair removal, similar to human with the OCD-spectrum disorder, trichotillomania. These mice first exhibit compulsive grooming, which turns pathological, resulting in hair removal and lesions at the over groomed sites. There are two principle sources of microglia in mammals, a resident population that is present in the brain early during embryogenesis prior to vascularization, and a second population derived from bone marrow that enters the brain after birth. Hoxb8 exclusively labels the second. Having demonstrated a direct relationship between defective microglia and a behavioral pathology, we are now positioned to determine how microglia affect behavior and most importantly how defective microglia leads to distinct behavioral pathology. One can imagine multiple mechanisms and the causality is likely to be multifaceted. We propose molecular approaches to determine how normal microglia differ from Hoxb8 mutant microglia. Genetic approaches will be used to determine if microglia deficiencies manifest a broader range of behavioral pathologies. Two-photon imaging will be used to examine the behavior of normal and mutant microglial filopodia. Finally, electrophysiological experiments will be used to determine if electrical contacts are made between microglia and neurons and whether these contacts are altered in Hoxb8 mutant mice. Further, if electrochemical contacts between microglia and neurons can be detected, can perturbations of microglia activity induce changes in neuronal activity? Through these multiple broad approaches we hope to provide insight into how non-neuronal cells in the brain, microglia, can so profoundly influence behavior and behavioral pathology.

描述（由申请人提供）：免疫功能障碍与许多神经精神疾病广泛相关，包括强迫症（OCD）、重度抑郁症、双向情感障碍、自闭症、精神分裂症和阿尔茨海默病。此外，全基因组关联研究的结果表明，其功能障碍与免疫功能障碍和/或信号传导有关的基因会导致上述精神障碍的风险增加。但上述关联的基础尚不明确，究竟是因还是果？治疗神经精神疾病的药物会影响免疫系统吗？我们已经鉴定出一只小鼠，其大脑免疫系统小胶质细胞有缺陷，似乎是导致独特病理行为的原因。此外，骨髓移植治愈了这只小鼠的病理行为。在这只小鼠中，我们将免疫系统缺陷与病理行为直接联系起来。 Hoxb8 突变的小鼠表现出意想不到的行为，表现为强迫性梳理毛发和脱毛，类似于患有强迫症谱系障碍（拔毛癖）的人类。这些小鼠首先表现出强迫性的梳理行为，然后变成病理性的，导致过度梳理部位的毛发脱落和损伤。哺乳动物中的小胶质细胞有两个主要来源，一种是在血管化之前的胚胎发生早期存在于大脑中的常驻群体，另一种是来自出生后进入大脑的骨髓的群体。 Hoxb8 专门标记了第二个。在证明了有缺陷的小胶质细胞与行为病理学之间的直接关系后，我们现在可以确定小胶质细胞如何影响行为，最重要的是有缺陷的小胶质细胞如何导致不同的行为病理学。人们可以想象多种机制，而且因果关系可能是多方面的。我们提出了分子方法来确定正常小胶质细胞与 Hoxb8 突变小胶质细胞的差异。遗传学方法将用于确定小胶质细胞缺陷是否表现出更广泛的行为病理学。双光子成像将用于检查正常和突变小胶质细胞丝状伪足的行为。最后，电生理学实验将用于确定小胶质细胞和神经元之间是否存在电接触，以及这些接触在 Hoxb8 突变小鼠中是否发生改变。此外，如果可以检测到小胶质细胞和神经元之间的电化学接触，小胶质细胞活动的扰动是否会引起神经元活动的变化？通过这些多种广泛的方法，我们希望深入了解大脑中的非神经元细胞（小胶质细胞）如何如此深刻地影响行为和行为病理学。