The Role of Purinergic Signaling in Microglia Birth and Maturation in the Adult Brain

项目摘要。小胶质细胞是大脑的免疫细胞，长期以来一直被认为具有重要作用 在脑部损伤和疾病期间。然而，最近的研究表明，小胶质细胞具有重要的作用。 在没有病理的情况下，维持大脑的动态平衡，支持发育中的神经元，并帮助 发育和可塑性过程中神经回路的重塑。这使得小胶质细胞成为治疗的靶点 神经回路发育或不适当重塑的疾病。尽管它们在大脑中很重要 健康和疾病，对小胶质细胞在脑内定植后如何自我维持知之甚少。 发展。这一知识是理解小胶质细胞如何在整个生命周期中维持其功能的基础。 生命的长短。虽然小胶质细胞是长寿细胞，但耗竭方法已经证明，成年的小胶质细胞 种群可以通过驻留细胞的增殖而迅速重组。因为这些研究已经 在固定的组织中进行，这一过程的动力学和机制尚不清楚。我建议确定如何 小胶质细胞在体内出生和成熟。我还将探索嘌呤能受体P2Y12在这一过程中的作用。 我假设小胶质细胞是由单个小胶质细胞分裂而来的，依赖于嘌呤能。 信号，以快速分化的形态和功能，以发挥其生理作用 大脑。为了验证这一假设，我将阐述两个相关但独立的目标。在目标1中，我有 开始测试小胶质细胞从单个存活的小胶质细胞的快速分裂重新填充的假设 正常情况下和实验耗尽后。我还证明了小胶质细胞对体验至关重要-- 成人视皮层的依赖可塑性。在目标2中，我将测试生理属性的假设 小胶质细胞的突起运动和小胶质细胞-突触的相互作用在小胶质细胞后不久恢复到基线水平 都是在成年后出生。我还将探讨P2Y12信号是否有助于这些属性的成熟 在新生的成年小胶质细胞中。最后，我将研究新生的小胶质细胞是如何迅速获得其功能的 支持视觉皮质中依赖经验的可塑性。这两个目标共同描述了小胶质细胞 在成年大脑皮质中增殖并维持动态平衡。因此，这一提议体现了一套新的技术 这使得对小胶质细胞自我更新动态的密切监测成为可能。我将在毕业后接受的培训 在学校执行第一个TO AIMS时，将为我在AIMS 3的博士后学习做准备，我将在那里 开展合作，确定治疗神经发育障碍的治疗目标。

Project Summary. Microglia are the brain’s immune cells and have long been appreciated for their critical roles during brain injury and disease. Recent studies, however, have demonstrated that microglia have important roles in the absence of pathology and serve to maintain brain homeostasis, support developing neurons and aid in the remodeling of neural circuitry during development and plasticity. This makes microglia a therapeutic target for diseases in which neural circuits either develop or remodel inappropriately. Despite their importance in brain health and disease, very little is known about how microglia self-maintain after they colonize the brain during development. This knowledge is fundamental to understanding how microglia maintain their functions throughout the lifespan. While microglia are long-lived cells, depletion methods have demonstrated that the adult microglial population can be rapidly reconstituted by the proliferation of resident cells. Because these studies have been carried out in fixed tissue the dynamics and mechanisms of this process are unclear. I propose to determine how microglia are born and mature in vivo. I will also explore the role of the purinergic receptor, P2Y12 in this process. I hypothesize that microglia are born by the division of single microglia and depend on purinergic signaling to rapidly differentiate morphologically and functionally to perform their physiological roles in the brain. In order to test this hypothesis, I will address two related but independent aims. In Aim 1, I have started to test the hypothesis that microglia repopulate from rapid division of single surviving microglia under normal conditions and after experimental depletion. I have also shown that microglia are critical to experience- dependent plasticity in the adult visual cortex. In Aim 2, I will test the hypothesis that the physiological attributes of microglia such as process motility and microglia-synapse interactions return to baseline soon after microglia are born in the adult. I will also explore whether P2Y12 signaling contributes to the maturation of these attributes in newly-born adult microglia. Lastly, I will examine how rapidly newly-born microglia acquire their functions that support experience-dependent plasticity in the visual cortex. Together these two aims characterize how microglia proliferate and maintain homeostasis in the adult cortex. Thus, this proposal embodies a new set of techniques that allows the close monitoring of the self-renewal dynamics of microglia. The training I will obtain in graduate school while performing the first to aims, will prepare me for my postdoctoral studies in Aim 3, where I will carry out collaborative work to determine therapeutic targets for the treatment of neurodevelopmental disorders.