Social regulation of oxidative stress in the brain

项目总结 社会环境对健康既有积极影响，也有消极影响。在许多群居动物中， 个人正在争夺更高的社会地位，这可能会导致具有不同社会压力的个人 社会地位有高有低。社会压力会导致大脑中的氧化应激，这是一个关键的机制 导致各种精神健康和神经退行性疾病。这项提议的总体目标是 描述社会地位对氧化应激的影响及其在整个大脑中的调节。虽然社会地位低下 地位可能是慢性压力的来源，高社会地位也是压力的来源--特别是在自然条件下 在这个领域，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 氧化应激源于社会应激和下丘脑-垂体-性腺之间的动态相互作用。 (HPG)轴。这种神经内分泌中心的激活会导致雄激素的释放，从而促进 竞争行为，但也是已知的调节氧化应激。我们将使用高度的 一种成熟的神经基因组学和集成动物模型系统--伯氏拟罗非鱼 行为，部分原因是神经内分泌系统相对于 哺乳动物。雄性伯顿沙门氏菌以两种可逆表型存在：显性表型和从属表型。占优势的男性 攻击性地保卫领地，由于HPG轴升高而拥有较大的性腺，并与雌性交配， 而从属的雄性则是非领地的，生殖受到抑制。社会地位可以很容易地 在复制组中被操纵和跟踪。该提案有以下具体目标：(1)测试 状态和HPG轴活动通过各种氧化标记物影响整个大脑的氧化应激模式 损伤和抗氧化剂防御。(2)决定社会地位和HPG轴的分子机制 活动会影响大脑的氧化应激。在完成这些目标后，我们将深入了解社交 状态和HPG轴活动在生物体水平上影响大脑健康和氧化平衡。该提案是 创新是因为它研究了大脑中氧化平衡的调节 一种新的模型系统中的从属个体，具有明显分层的优势等级。建议数 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有因果关系， 包括抑郁症和与年龄相关的脑部疾病。我们的结果将提供有用的信息，最终将 对改善公共健康很重要。这项拟议的研究将使本科生接触到 解决生物医学相关问题的假设驱动的研究。

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.