Brain Irradiation Affects Neuronal Function

脑部辐射影响神经元功能

• 批准号: 7846906
• 负责人: Susanna Rosi
• 金额: $ 32.06万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846906
• 关键词: Adverse effects; Affect; Animals; Antisense Oligonucleotides; Area; Behavioral; Brain; Brain Injuries; Brain Neoplasms; Brain region; Chronic; Cognitive deficits; Coupling; Cranial Irradiation; Cytoskeleton; Data; Development; Dose; Evolution; Exhibits; Functional disorder; Gene Expression; Genetic Transcription; Glutamates; Goals; Hippocampus (Brain); Image; Immediate-Early Genes; Impaired cognition; Injury; Kinetics; Lead; Learning; Long-Term Potentiation; Medial; Mediating; Memory; Memory impairment; Messenger RNA; Microglia; Molecular; Mus; Neuraxis; Neuronal Dysfunction; Neuronal Injury; Neurons; Oxidative Stress; Pathogenesis; Performance; Physiological; Play; Probability; Process; Proteins; Quality of life; Radiation; Relative (related person); Reporting; Research Infrastructure; Risk; Role; Severities; Synapses; Synaptic Transmission; Temporal Lobe; Testing; Therapeutic; Time; Tissues; Translations; Vision; base; brain irradiation injury; brain tissue; chemokine receptor; cognitive function; dentate gyrus; experience; genetic manipulation; information processing; insight; irradiation; memory process; mouse model; neurogenesis; neuroinflammation; neuronal patterning; novel; prevent; protein expression; public health relevance; relating to nervous system; therapy development

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.

描述（由申请人提供）：在这项研究中，我们建议使用即时早期基因（IEG）表达成像来评估脑辐射对神经元功能的影响，长期目标是确定IEG弧（活性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受到影响的。治疗性辐射通常用于治疗脑肿瘤，但会对正常脑组织造成严重损害。一般来说，高剂量照射后会发生明显的组织损伤，但低剂量照射后可能不会发生这种组织损伤，然而，海马体依赖性认知能力下降，包括空间学习和记忆巩固的缺陷，可能会发展。这种影响的严重程度取决于给予内侧颞叶的剂量，内侧颞叶包含海马体，一个负责学习和记忆的区域。辐射引起的认知缺陷的发病机制尚不清楚，但可能是多方面的，包括神经发生改变、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种神经过程和突触传递。我们之前对慢性神经炎症的分析表明，突触活动依赖蛋白的消耗可能在认知能力下降中起关键作用。在这种情况下，特别重要的是观察直接早期基因产物Arc的变化，其表达已被用于解剖涉及编码空间和环境信息的细胞网络。此外，慢性激活的小胶质细胞的存在与Arc表达的中断和认知功能障碍有关。激活的小胶质细胞可能会改变与学习和记忆巩固有关的神经活动与大分子合成的耦合。因此，Arc与一些关键因素密切相关，这些因素最近被描述为在辐射引起的认知障碍的发展中起着促进作用（如果不是因果作用）。根据Arc在mRNA和蛋白表达水平上的分子分布，我们假设脑辐照会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性的。最后，我们断言这些变化受到活化小胶质细胞存在的影响，我们将使用趋化因子受体2缺乏的小鼠来获得这种关系的机制见解。考虑到Arc转录、易位和翻译的时间动力学，我们将能够为与认知功能相关的基因表达的转录后基础设施提供新的视角。这些研究将提供关于电离辐射如何影响大脑神经元功能的新信息。这些类型的数据目前无法获得，但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策略来说，这是至关重要的第一步。公共卫生相关性：虽然颅照射通常用于治疗脑肿瘤，但这种治疗也很可能产生严重影响生活质量的不良影响（即认知障碍）。本研究将为电离辐射如何影响与学习记忆过程相关的脑区神经元功能的机制提供新的信息。这些类型的数据目前无法获得，但对于确定特定中枢神经系统相关影响的风险和制定管理辐射介导的脑损伤的潜在策略至关重要。