Social regulation of oxidative stress in the brain

项目摘要 社会环境对健康既有积极的影响，也有消极的影响。在许多群居动物中， 个人都在为高社会地位而竞争，这可能会导致具有不同社会压力的个人 社会地位高低都有。社会压力会引起大脑的氧化应激，这是一个关键机制 导致各种心理健康和神经退行性疾病。本建议的总体目标是 描述社会地位对氧化应激及其在大脑中的调节的影响。虽然低社会 地位可能是慢性压力的来源，高社会地位也会带来压力--特别是在自然条件下 捍卫社会主导地位是具有挑战性的。我们假设社会地位对大脑的影响 氧化应激来自社会应激和下丘脑-垂体-性腺之间的动态相互作用。 (HPG)轴线这个神经内分泌中心的激活导致雄激素的释放， 竞争行为，但也已知调节氧化应激。我们将使用高度的 社会性丽鱼Astatotilapia burtoni--一个成熟神经基因组学和综合动物模型系统 行为，部分原因是神经内分泌系统的大同线性和共享同源性， 哺乳动物雄性A. Burtoni存在两种可逆表型：显性和从属。占主导地位的男性 积极捍卫领土，由于HPG轴上调而具有大性腺，并与雌性交配， 而从属的雄性则没有领土意识，生殖能力受到抑制。社会地位很容易 在重复组中进行操纵和跟踪。该建议有以下具体目标：（1）测试如何社会 状态和HPG轴活动影响整个大脑的氧化应激模式， 抗氧化防御。(2)确定社会地位和HPG轴的分子机制 活动影响脑氧化应激。在完成这些目标后，我们将深入了解社会如何 状态和HPG轴活动影响大脑健康和生物体水平的氧化平衡。该提案 创新，因为它研究了大脑中氧化平衡的调节， 在一个新的模型系统与明显分层的统治阶层的从属个人。拟议 这项工作意义重大，因为大脑中的氧化应激与一系列精神病理学有因果关系， 包括抑郁症和与年龄相关的脑部疾病。我们的研究结果将提供有用的信息， 对改善公共卫生很重要。拟议的研究将使本科生接触到 假设驱动的研究，解决生物医学相关的问题。

PROJECT SUMMARY The social environment can have both positive and negative impacts on health. In many social animals, individuals are competing for high social status, which can result in distinct social stressors for individuals with both high and low social status. Social stress can cause oxidative stress in the brain, which is a key mechanism driving a variety of mental health and neurodegenerative diseases. The overall objective of this proposal is to characterize the impact of social status on oxidative stress and its regulation across the brain. While low social status can be a source of chronic stress, high social status is also stressful - especially in natural conditions where defending social dominance is challenging. We hypothesize that the impact of social status on brain oxidative stress arises from a dynamic interplay between social stress and the hypothalamic-pituitary-gonadal (HPG) axis. Activation of this neuroendocrine center leads to the release of androgens, which facilitates competitive behavior, but is also known to modulate oxidative stress. We will test our hypothesis using the highly social cichlid fish Astatotilapia burtoni, a well-established model system for neurogenomics and integrated animal behavior, due in part to the large synteny and shared homologies of the neuroendocrine system relative to mammals. Male A. burtoni exist as two reversible phenotypes: dominant and subordinate. Dominant males aggressively defend a territory, have large gonads due to an upregulated HPG axis, and mate with females, while subordinate males are nonterritorial and reproductively suppressed. Social status can be readily manipulated and tracked in replicate groups. The proposal has the following specific aims: (1) Test how social status and HPG axis activity impact oxidative stress patterns across the brain using various markers of oxidative damage and antioxidant defense. (2) Determine the molecular mechanisms by which social status and HPG axis activity influence brain oxidative stress. At the completion of these aims, we will provide insights into how social status and HPG axis activity impact brain health and oxidative balance at the organismal level. The proposal is innovative because it investigates the regulation of oxidative balance in the brain in both dominant and subordinate individuals in a novel model system with a distinctly stratified dominance hierarchy. The proposed work is significant because oxidative stress in the brain has been causally linked to a range of psychopathologies, including depression and age-related brain disease. Our results will provide useful information that will ultimately be important for improving public health. The proposed research will expose undergraduate students to hypothesis-driven research addressing biomedically relevant questions.