From Defective Microglia to Cortical Activity and Pathological Behavior

描述(申请人提供)：免疫功能障碍被广泛地与许多神经精神疾病联系在一起，包括强迫症(OCD)、严重抑郁症、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/或信号转导有关的基因，有助于增加上述精神障碍的风险。然而，上述关联的基础尚不清楚，究竟是因果关系还是结果关系？治疗神经精神障碍的药物会影响免疫系统吗？我们已经确定了一只小鼠，其中有缺陷的小胶质细胞，大脑的免疫系统，似乎是一种独特的病理行为的原因。此外，骨髓移植可以治愈这只小鼠的病理行为。在这只小鼠中，我们已经将免疫系统的缺陷与病理行为直接联系起来。Hoxb8基因突变的小鼠表现出意想不到的行为，表现为强迫梳妆和脱毛，类似于患有强迫症谱系障碍的人类，毛发狂热。这些小鼠首先表现出强迫性的梳理，这会变成病理，导致过度梳理的部位脱毛和损伤。哺乳动物的小胶质细胞有两个主要来源，一个是在胚胎发育早期血管形成之前就存在于大脑中的常驻群体，另一个是出生后进入大脑的来自骨髓的第二个群体。Hoxb8独家标记第二种。在证明了小胶质细胞缺陷与行为病理之间的直接关系后，我们现在可以确定小胶质细胞如何影响行为，最重要的是，小胶质细胞缺陷如何导致不同的行为病理。人们可以想象多种机制，其中的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突变小胶质细胞的不同之处。遗传学方法将被用来确定小胶质细胞缺陷是否表现出更广泛的行为病理。双光子成像将被用来检查正常和突变的小胶质细胞丝状足的行为。最后，电生理学实验将被用来确定小胶质细胞和神经元之间是否有电接触，以及这些接触在Hoxb8突变小鼠中是否发生了改变。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导致神经元活动的变化？通过这些广泛的方法，我们希望深入了解大脑中的非神经细胞--小胶质细胞--如何如此深刻地影响行为和行为病理学。

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.