Strohm Alexandra O, Oldfield Sadie, Hernady Eric, Johnston Carl J, Marples Brian, O'Banion M Kerry, Majewska Ania K
Departments of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Neuroscience, University of Rochester Medical Center, Rochester, NY, 14642, USA.
Brain Behav Immun Health. 2024 Nov 25;43:100911. doi: 10.1016/j.bbih.2024.100911. eCollection 2025 Feb.
Patients receiving cranial radiation therapy experience tissue damage and cognitive deficits that severely decrease their quality of life. Experiments in rodent models show that these adverse neurological effects are in part due to functional changes in microglia, the resident immune cells of the central nervous system. Increasing evidence suggests that experimental manipulation of microglial signaling can regulate radiation-induced changes in the brain and behavior. Furthermore, many studies show sex-dependent neurological effects of radiation exposure. Despite this, few studies have used both males and females to explore how sex and microglial function interact to influence radiation effects on the brain. Here, we used a system levels approach to examine how deficiencies in purinergic and fractalkine signaling, two important microglial signaling pathways, impact brain proteomic and behavioral profiles in irradiated and control male and female mice. We performed a comprehensive analysis of the cortical proteomes from irradiated and control C57BL/6J, P2Y12-/-, and CX3CR1-/- mice of both sexes using multiple bioinformatics methods. We identified distinct proteins and biological processes, as well as behavioral profiles, regulated by sex, genotype, radiation exposure, and their interactions. Disrupting microglial signaling, had the greatest impact on proteomic expression, with CX3CR1-/- mice showing the most distinct proteomic profile characterized by upregulation of CX3CL1. Surprisingly, radiation exposure caused relatively smaller proteomic changes in glial and synaptic proteins, including Rgs10, Crybb1, C1qa, and Hexb. While we observed some radiation effects on locomotor behavior, biological sex as well as loss of P2Y12 and CX3CR1 signaling had a stronger influence on locomotor outcomes in our model. Lastly, loss of P2Y12 and CX3CR1 strongly regulated exploratory behaviors. Overall, our findings provide novel insights into the molecular pathways and proteins that are linked to P2Y12 and CX3CR1 signaling, biological sex, radiation exposure, and their interactions.
接受颅脑放射治疗的患者会经历组织损伤和认知缺陷，这严重降低了他们的生活质量。啮齿动物模型实验表明，这些不良神经效应部分归因于小胶质细胞（中枢神经系统的常驻免疫细胞）的功能变化。越来越多的证据表明，对小胶质细胞信号传导的实验性操作可以调节辐射诱导的大脑和行为变化。此外，许多研究表明辐射暴露存在性别依赖性神经效应。尽管如此，很少有研究同时使用雄性和雌性动物来探究性别和小胶质细胞功能如何相互作用以影响辐射对大脑的作用。在这里，我们采用系统水平的方法来研究嘌呤能和趋化因子信号传导（两种重要的小胶质细胞信号通路）的缺陷如何影响受辐照和对照的雄性和雌性小鼠的脑蛋白质组学和行为特征。我们使用多种生物信息学方法对受辐照和对照的两性C57BL/6J、P2Y12基因敲除小鼠和CX3CR1基因敲除小鼠的皮质蛋白质组进行了全面分析。我们确定了受性别、基因型、辐射暴露及其相互作用调节的不同蛋白质和生物学过程，以及行为特征。破坏小胶质细胞信号传导对蛋白质组学表达的影响最大，CX3CR1基因敲除小鼠表现出最独特的蛋白质组学特征，其特征是CX3CL1上调。令人惊讶的是，辐射暴露在神经胶质和突触蛋白（包括Rgs10、Crybb1、C1qa和Hexb）中引起的蛋白质组学变化相对较小。虽然我们观察到辐射对运动行为有一些影响，但在我们的模型中，生物性别以及P2Y12和CX3CR1信号的缺失对运动结果的影响更强。最后，P2Y12和CX3CR1的缺失强烈调节探索行为。总体而言，我们的研究结果为与P2Y12和CX3CR1信号传导、生物性别、辐射暴露及其相互作用相关的分子途径和蛋白质提供了新的见解。
