From Defective Microglia to Cortical Activity and Pathological Behavior

描述（由申请人提供）：免疫功能障碍与许多神经精神疾病有广泛的联系，包括强迫症（OCD）、重度抑郁症、双相情感障碍、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增加患上述精神障碍的风险。然而，上述关联的基础尚不清楚，哪个是因果关系？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老鼠，它的小胶质细胞（大脑的免疫系统）有缺陷，似乎导致了一种独特的病理行为。此外，骨髓移植治疗了这只老鼠的病理行为。在这只老鼠身上，我们直接将免疫系统缺陷与病理行为联系起来。携带Hoxb8基因突变的小鼠表现出意想不到的行为，表现为强迫性梳洗和脱毛，类似于患有强迫症谱系障碍、拔毛癖的人类。这些老鼠首先表现出强迫性梳理，然后变成病态，导致毛发脱落和过度梳理部位的损伤。哺乳动物的小胶质细胞主要有两种来源，一种是在胚胎形成之前的早期大脑中存在的常驻群体，另一种是在出生后进入大脑的骨髓中产生的群体。Hoxb8专门标记第二种。在证明了有缺陷的小胶质细胞和行为病理之间的直接关系之后，我们现在要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。人们可以想象多种机制，其因果关系可能是多方面的。我们提出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的小胶质丝状足的行为。最后，电生理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，以及这些接触是否在Hoxb8突变小鼠中被改变。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，那么小胶质细胞活动的扰动是否会引起神经元活动的变化？通过这些广泛的方法，我们希望能够深入了解大脑中的非神经元细胞，小胶质细胞，是如何深刻地影响行为和行为病理学的。

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.