STRESS NEUROPEPTIDES, DEPRESSION AND AGING

描述（改编自申请人的摘要）：知之甚少 免疫和心理压力对大脑的分子影响 在老年人中，更少有人知道他们在老年人中的作用。 晚年抑郁症的发病机制。 如果知道这些信息， 潜在的应用，以改善诊断和治疗晚期 抑郁症会很严重 然而，很少有调查人员 他们能够将分子和临床方法与研究相结合 涉及老年人口。 研究和教育 本K01应用程序的组件将提供必要的培训， 申请人成为这样的调查员;这将涉及密切 与基础研究和临床导师的联系。 研究计划是 基础科学为导向，是以应激神经肽为前提的 下丘脑和杏仁核中的神经系统随着年龄的增长而过度活跃。 肽能过度活化被认为反映了细胞凋亡的总体减少。 功能性CNS储备，因此在晚期 生活抑郁症 待检验的假设包括：1）白细胞介素-1 对老年大鼠给药导致下丘脑中更大的激活 神经肽应激系统; 2）这与减少 海马皮质类固醇受体; 3）老年大鼠的束缚应激导致 杏仁核CRF系统的激活程度更高; 4）这与 杏仁核磷酸化CREB过度激活 为了检验这些假设， 对老年大鼠进行以下具体措施并进行比较 中年和青年大鼠：CRF和加压素基因， 将在下丘脑和垂体中测量肽表达 中枢白细胞介素-1（IL-1）激发后。 海马皮质类固醇 结合也将在中心IL 1后测量。 附加的一组 动物将被给予束缚应激;行为和分子 将沿着杏仁核CRF系统的测量， 磷酸化CERB水平。 小鼠模型的开发也将启动 因为这个物种可以进行转基因操作。 而 进行基础研究，临床导师将监督 研究计划，并为申请人提供临床指导 心理神经免疫学和晚年抑郁症 此外，他们将 为申请人提供指导，以应用 对人类的研究。 完成5年计划的目的是 使申请人成为能够整合分子的独立研究者 神经内分泌生理学研究与临床老年精神病学 research.

DESCRIPTION (Adapted from the Applicant's Abstract): Very little is known about the molecular impact of immune and psychological stresses on the brain in the elderly and even less is known about the role of their in the pathogenesis of late life depression. Were this information known, the potential applications toward improving the diagnoses and treatment of late depression would be profound. There are, however, very few investigators who are able to integrate molecular and clinical approaches with studies involving elderly human populations. The research and educational components of this K01 application will provide the necessary training for the applicant to become such an investigator; this will involve close contact with basic research and clinical mentors. The research plan is basic science oriented and is based on the premise that stress neuropeptide systems in the hypothalamus and amygdala are overactivated with aging. Peptidergic overactivation is thought to reflect an overall decrease in functional CNS reserve and thus plays a role in the pathogenesis of late life depression. The hypotheses to be tested include: 1) Interleukin-1 administration to aged rats leads to a greater activation in hypothalamic neuropeptide stress systems; 2) this is associated with decreases in hippocampal corticosteroid receptors; 3) Restraint stress in aged rats leads to a greater activation in amygdalar CRF systems; and, 4) this is associated with overactivation of amygdalar phospho CREB. To test these hypotheses, the following specific measures will be made in old age rats and compared with rats of middle age and young adulthood: CRF and vasopressin gene and peptide expression will be measured in the hypothalamus and pituitary following central interleukin-1 (IL1) challenge. Hippocampal corticosteroid binding will also be measured following central IL1. An additional set of animals will be administered restraint stress; behavioral and molecular measurements of amygdalar CRF systems will be made along with amygdalar phosphoCERB levels. The development of mouse models will also be initiated given that this species is amenable to transgenic manipulation. While carrying out the basic research, the clinical mentors will oversee the research program and also provide the applicant with tutorials in clinical psychoneuroimmunology and late life depression. In addition, they will provide the applicant with guidance, to apply the molecular findings of the research to human populations. Completion of the 5-year program aims to make the applicant an independent investigator who can integrate molecular neuroendocrinology physiology research with clinical geropsychiatry research.