Myeloid cells and radiation-induced memory deficits in rodent glioma model: sex and age effects

项目摘要/摘要 电离辐射通常用于治疗原发性和转移性脑肿瘤，并可引起 后遗症的数量，包括进行性认知功能障碍。这些认知变化尤其是 儿童时期接受过辐射治疗的人病情严重。由此产生的影响的范围和性质 认知缺陷可能会受到年龄、治疗和性别的影响。造成这种差异的神经生物学原因 是未知的，而且很少有实验研究解决这个问题。啮齿动物体内的电离辐射一直是 始终如一地被证明激活了几个可以影响多个神经的神经炎性信号级联反应 突触过程和突触传递，最终扰乱海马体功能。神经炎症， 以脑内驻留的小胶质细胞激活和外周来源的单核细胞募集为特征 (统称为“髓系细胞”)一直以来都与认知功能的丧失有关。 辐射后的小鼠。目前还没有预防或治疗辐射引起的认知障碍的治疗方法。 功能障碍。尽管有广泛的临床证据将分次脑照射与认知缺陷联系起来， 在这一观察的生物学基础上仍有未回答的空白：激活的机制/S 炎症反应影响认知功能，以及年龄和性别的影响。此外，没有 总结最常见临床情景特征的临床前模型：中央型患者 神经系统(CNS)肿瘤。我们的最终治疗目标是预防和治疗观察到的认知变化。 分次全脑照射(FWBI)后。我们假设成分的变化和 脑照射后髓系细胞的功能可预防和挽救认知功能障碍 通过对突触产生持久的影响。这项提议的翻译目标是证明 通过短暂的小胶质细胞耗尽来重置免疫系统可以防止记忆缺陷的长期发展 在一个脑瘤模型中，该模型旨在模仿临床环境中使用的传统治疗范例。具体的 支持我们假设的目标是： 1.建立FWBI对年龄和性别对小鼠记忆和突触组成的影响 免疫活性小鼠脑胶质瘤模型。 2.确定髓系细胞在FWBI所致记忆障碍中的作用。 3.评价髓系细胞作为FWBI后永久性记忆障碍的机制驱动因素的作用。 关于外周辐射诱导的病理生理学的演变，我们知之甚少。 衍生巨噬细胞聚集或炎症及其与突触和认知改变的关系 功能。我们的最终治疗目标是改变辐射损伤后观察到的认知变化。

Project Summary/Abstract Ionizing irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. These cognitive changes are particularly severe in individuals who were treated with radiation during childhood. The extent and nature of the resulting cognitive deficits may be influenced by age, treatment and gender . The neurobiological reason for this difference is unknown, and very few experimental studies have addressed this issue. Ionizing radiation in rodents has been consistently shown to activate several neuroinflammatory signaling cascades that can impact multiple neural processes and synaptic transmission, ultimately disrupting hippocampal function. Neuroinflammation, characterized by activation of brain resident microglia and recruitment of peripherally derived monocytes (collectively referred to as `myeloid cells'), has been consistently associated with the loss of cognitive function in mice after radiation. There are still no treatments for preventing or treating radiation-induced cognitive dysfunction. Despite the extensive clinical evidence linking fractionated brain irradiation with cognitive deficits, there are still unanswered gaps in the biologic basis of this observation: the mechanism/s by which activation of the inflammatory response affect cognitive function, and the effect of age and sex. Furthermore, there are no pre-clinical models that recapitulate the features of the most common clinical scenario: patients with central nervous system (CNS) tumors. Our final therapeutic goal is to prevent and treat the cognitive changes observed after fractionated whole-brain irradiation (fWBI) injury. We hypothesize that changes in the composition and function of myeloid cells following brain irradiation can both prevent and rescue cognitive deficits through durable effects on synapses. The translational objective of this proposal is to demonstrate that resetting the immune system by brief microglia depletion prevents the long-term development of memory deficits in a brain tumor model designed to mimic conventional treatment paradigms used in clinical settings. The specific aims in support of our hypothesis are: 1. Establish the effects of fWBI on memory and synaptic composition as a function of age and sex in an immunocompetent mouse glioma model. 2. Determine the role of myeloid cells in the development of fWBI-induced memory deficits. 3. Evaluate the role of myeloid cells as a mechanistic driver of the permanent memory deficits after fWBI. Very little is known in regard to the evolution of radiation induced pathophysiology in the context of peripherally derived macrophage accumulation or inflammation, and how this relates to altered synaptic and cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.