Brain Irradiation Affects Neuronal Function

描述(申请人提供)：在这项研究中，我们建议使用即刻早期基因(IEG)表达成像来评估脑照射对神经元功能的影响，长期目标是确定IEG Arc(活动调节细胞骨架相关蛋白)在辐射诱导的神经元缺陷的演变中是如何影响的。治疗性照射通常用于治疗脑肿瘤，但会对正常脑组织造成重大损害。一般来说，相对较高剂量的照射后会出现明显的组织损伤，但在较低剂量照射后，这种组织损伤可能不会发生，然而，海马体依赖的认知能力下降，包括空间学习和记忆巩固方面的障碍，可能会发生。这种影响的严重程度取决于给内侧颞叶的剂量，内侧颞叶包含负责学习和记忆的海马体。辐射所致认知障碍的发病机制尚不清楚，但可能是多方面的，涉及神经发生改变、慢性神经炎症和慢性氧化应激，所有这些因素都可以影响多个神经过程和突触传递。我们之前对慢性神经炎的分析表明，突触活性依赖蛋白的枯竭可能在认知能力下降中发挥关键作用。在这种情况下，特别重要的是观察到即刻早期基因产物Arc的变化，其表达已被用于剖析参与编码空间和上下文信息的细胞网络。此外，长期激活的小胶质细胞的存在与Arc表达中断和认知功能障碍有关。激活的小胶质细胞可能改变神经活动与与学习和记忆巩固有关的大分子合成的耦合。因此，Arc与最近被描述为在辐射诱导的认知障碍的发展中起贡献作用(如果不是因果作用)的关键因素密切相关。我们假设，通过Arc在mRNA和蛋白质表达水平上的分子分布来评估，脑照射将对神经元功能产生不利影响。我们进一步认为，这将反映在神经发生和行为表现的改变上，并且这种影响将是剂量依赖的。最后，我们断言这些变化受到激活的小胶质细胞的存在的影响，我们将使用缺乏趋化因子受体2的小鼠来从机制上深入了解这种关系。鉴于Arc转录、易位和翻译的良好时间动力学，我们将能够提供新的视角，了解与认知功能相关的基因表达潜在机制的转录后基础结构。这些研究将提供有关电离辐射如何影响大脑神经功能的新信息。这些类型的数据目前无法获得，对于确定特定中枢神经系统相关影响的风险和制定管理放射性脑损伤的潜在战略来说，这是至关重要的第一步。公共卫生相关性：虽然颅脑照射通常用于脑肿瘤的治疗，但这种治疗很可能也会产生严重影响生活质量的不良反应(即认知障碍)。这项拟议的研究将提供有关电离辐射如何影响与学习和记忆过程相关的脑区神经功能机制的新信息。这些类型的数据目前无法获得，对于确定特定中枢神经系统相关影响的风险以及制定管理辐射介导的脑损伤的潜在战略至关重要。

DESCRIPTION (provided by applicant): In this study we propose to use immediate-early gene (IEG) expression imaging to assess the effects of brain irradiation on neuronal functioning, with the long term goal of identifying how the IEG Arc (activity regulated cytoskeleton-associated protein) is affected in the evolution of radiation- induced neuronal deficits. Therapeutic irradiation is commonly used to treat brain tumors but can cause significant damage to normal brain tissues. In general, overt tissue injury occurs after relatively high doses of irradiation, but after lower doses such tissue damage may not occur, however, hippocampus-dependent cognitive decline, including deficits in spatial learning and memory consolidation, can develop. The severity of such effects depends on the dose delivered to the medial temporal lobes, which contain the hippocampus, a region responsible for learning and memory. The pathogenesis of radiation-induced cognitive deficits is poorly understood, but is likely multifaceted, involving altered neurogenesis, chronic neuroinflammation, and chronic oxidative stress, all factors that can impact multiple neural processes and synaptic transmission. Our previous analyses of chronic neuroinflammation suggest that the depletion of synaptic activity-dependent proteins may play a critical role in cognitive decline. Particularly important in this context is the observation of alterations in the immediate-early gene product Arc, the expression of which has been used to dissect, cellular networks involved in encoding spatial and contextual information. Furthermore, the presence of chronically activated microglia is associated with the disruption of Arc expression and cognitive dysfunctions. Activated microglia may alter the coupling of neural activity with macromolecular synthesis implicated in learning and memory consolidation. Thus, Arc is closely associated with critical factors recently described as playing contributory if not causal roles in the development of radiation-induced cognitive impairments. We hypothesize that irradiation of the brain will adversely affect neuronal function, as assessed by the molecular distribution of Arc at the level of mRNA and protein expression. We further contend that this will be reflected in alterations in neurogenesis and behavioral performances, and that such effects will be dose dependent. Finally, we assert that these changes are influenced by the presence of activated microglia, and we will use mice deficient in chemokine receptor 2 to gain mechanistic insight into this relationship. Given the well-established temporal kinetics of Arc transcription, translocation and translation, we will be able to provide novel sight into the post-transcriptional infrastructure of gene expression underlying mechanisms associated with cognitive function. These studies will give new information about how ionizing irradiation impacts neuronal function in the brain. These types of data are currently unavailable and represent an essential first step for determining the risks of specific CNS-related effects and for the development of potential strategies to manage radiation brain injury. PUBLIC HEALTH RELEVANCE: Although cranial irradiation is commonly used for the treatment of brain tumors, there is a significant probability that this treatment also produces adverse effects severely impacting quality of life (i.e. cognitive impairments). The proposed studies will provide new information about how ionizing irradiation impacts mechanisms of neuronal function in brain region associated with learning and memory processes. These types of data are currently unavailable and are essential for determining the risks of specific central nervous system related effects and for the development of potential strategies to manage radiation-mediated brain injury.