Brain Irradiation Affects Neuronal Function

脑部辐射影响神经元功能

• 批准号: 8256616
• 负责人: Susanna Rosi
• 金额: $ 31.1万
• 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/8256616
• 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; Health; 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; mRNA Expression; memory process; mouse model; neurogenesis; neuroinflammation; neuronal patterning; novel; prevent; protein expression; 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，我们建议使用直接至上的基因（IEG）表达成像来评估脑辐照对神经元功能的影响，其长期目标是确定IEG ARC（活性调节的细胞骨架相关蛋白）如何在辐射诱导的神经元降低的神经元素的进化中影响。治疗辐射通常用于治疗脑肿瘤，但会对正常脑组织造成重大损害。通常，在相对较高的辐射剂量后发生明显的组织损伤，但是在较低剂量后，可能不会发生这种组织损伤，但是，海马依赖性认知能力下降，包括空间学习和记忆巩固的缺陷。这种效果的严重性取决于将剂量传递给内侧颞叶，后者包含海马，这是负责学习和记忆的区域。辐射引起的认知缺陷的发病机理知之甚少，但可能是多方面的，涉及改变神经发生，慢性神经炎症和慢性氧化应激，所有因素都会影响多个神经过程和突触传播。我们先前对慢性神经炎症的分析表明，突触活性依赖性蛋白质的消耗可能在认知下降中起关键作用。在这种情况下，尤其重要的是观察到直接基因产物弧的变化，其表达已被用于剖析与编码空间和上下文信息有关的细胞网络。此外，长期活化的小胶质细胞的存在与弧表达和认知功能障碍的破坏有关。活化的小胶质细胞可能会改变与学习和记忆巩固有关的大分子合成的神经活动的耦合。因此，ARC与最近描述为发挥作用的关键因素密切相关，即使不是因果关系在辐射引起的认知障碍的发展中的作用。我们假设大脑的照射会对神经元功能产生不利影响，如通过mRNA和蛋白质表达水平的ARC的分子分布评估。我们进一步争辩说，这将反映在神经发生和行为表现的改变中，并且这种影响将取决于剂量。最后，我们断言这些变化受活化的小胶质细胞的影响，我们将使用缺乏趋化因子受体2的小鼠来获得对这种关系的机械洞察力。鉴于弧度转录，易位和翻译的良好时间动力学，我们将能够将新颖的视力提供到与认知功能相关的基因表达的转录后基础架构中。这些研究将提供有关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不可用，这是确定特定CNS相关效果的风险以及制定管理辐射脑损伤的潜在策略的重要第一步。公共卫生相关性：尽管颅骨辐照通常用于治疗脑肿瘤，但这种治疗的可能性也很可能会产生严重影响生活质量（即认知障碍）的不良反应。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有关的大脑区域中神经元功能机制的新信息。这些类型的数据目前不可用，对于确定特定中枢神经系统相关效应的风险以及管理辐射介导的脑损伤的潜在策略至关重要。