The role of purinergic signaling in mediating the dynamics of microglia repopulation following depletion in the adult cortex in vivo

体内成人皮质耗竭后嘌呤能信号在介导小胶质细胞再生动态中的作用

• 批准号: 10194309
• 负责人: Monique Shanice Mendes
• 金额: $ 0.81万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10194309
• 关键词: Address; Adult; Animal Model; Birth; Brain; Brain Diseases; Brain Injuries; Cells; Chronic; Collaborations; Development; Disease; Elements; Environment; Freedom; Functional disorder; Generations; Genetic; Growth; Health; Homeostasis; Image; Imaging Device; Immune; Knowledge; Leadership; Learning; Longevity; Measures; Mediating; Mentors; Methods; Microglia; Monitor; Morphology; Mus; Nervous system structure; Neurodevelopmental Disorder; Neurons; Ocular Dominance; Optics; Pathology; Pharmacology; Physiological; Population; Positioning Attribute; Process; Proliferating; Purinoceptor; Research; Research Design; Research Personnel; Rodent Model; Role; Schizophrenia; Schools; Self Perception; Signal Transduction; Synapses; Technical Expertise; Techniques; Testing; Tissues; Training; Vision; Visual Cortex; Work; awake; brain health; career; cell motility; drug discovery; experience; experimental study; functional plasticity; imaging approach; in vivo; in vivo imaging; in vivo two-photon imaging; insight; interest; neural circuit; novel; novel therapeutics; pre-clinical; preclinical study; reconstitution; response; self-renewal; skills; therapeutic target; translational study

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.

项目摘要。小胶质细胞是大脑的免疫细胞，长期以来一直因其关键作用而受到重视 在脑损伤和疾病中。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，并用于维持脑内稳态，支持发育中的神经元，并有助于 在发育和可塑性过程中重塑神经回路。这使得小胶质细胞成为一个治疗靶点， 神经回路发展或重塑不当的疾病。尽管它们在大脑中的重要性 尽管小胶质细胞在健康和疾病中的作用，但人们对它们在大脑中定植后如何自我维持知之甚少。 发展这些知识对于理解小胶质细胞如何在整个过程中维持其功能至关重要 寿命虽然小胶质细胞是长寿命细胞，但耗竭方法已经证明成年小胶质细胞 细胞群可以通过驻留细胞的增殖快速重建。因为这些研究 在固定组织中进行，该过程的动力学和机制尚不清楚。我建议确定 小胶质细胞在体内出生和成熟。我还将探索嘌呤能受体P2 Y12在这个过程中的作用。 我推测小胶质细胞是由单个小胶质细胞分裂产生的，并依赖于嘌呤能。 在形态和功能上快速分化以执行其生理作用的信号， 大脑为了验证这个假设，我将讨论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中重新繁殖的假设， 正常条件下和实验耗尽后。我也证明了小胶质细胞对体验至关重要- 成人视皮层的依赖性可塑性在目标2中，我将检验生理属性 小胶质细胞的运动性和小胶质细胞-突触相互作用在小胶质细胞 出生在成年人。我还将探讨P2 Y12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如何快速获得它们的功能， 支持视觉皮层中依赖经验的可塑性。这两个目标共同描述了小胶质细胞如何 在成年人的大脑皮层中增殖并维持体内平衡。因此，该建议体现了一套新的技术 这使得我们可以密切监测小胶质细胞的自我更新动力学。我将在研究生阶段获得的培训 学校，而执行第一个目标，将准备我在我的博士后研究目标3，在那里我将进行 我们的合作工作，以确定治疗神经发育障碍的治疗目标。