STRESS NEUROPEPTIDES, DEPRESSION AND AGING

描述(改编自申请者摘要)：知之甚少 关于免疫和心理压力对大脑的分子影响 对老年人的影响更是少之又少 老年抑郁症的发病机制。如果这个信息是已知的， 在提高晚期癌症诊断和治疗方面的潜在应用 大萧条的影响将是深远的。然而，调查人员很少。 谁能够将分子和临床方法与研究相结合 涉及到老年人口。研究和教育 此K01应用程序的组件将提供必要的培训 申请者要成为这样的调查员；这将涉及到 联系基础研究和临床导师。研究计划是 基础科学是以应激神经肽为前提的 随着年龄的增长，下丘脑和杏仁核系统过度激活。 多肽能过度激活被认为反映了 功能性中枢神经系统储备在迟发性脑梗塞发病机制中的作用 生活忧郁症。需要检验的假设包括：1)白介素1 老年大鼠给药后下丘脑的激活 神经肽应激系统；2)这与体内 海马区皮质类固醇受体；3)老年大鼠束缚应激导致 与杏仁核CRF系统的更大激活有关；以及，4)这与 杏仁核磷酸化CREB过度激活。为了检验这些假设， 将在老年大鼠身上采取以下具体措施并进行比较 中青年大鼠CRF和加压素基因及 将在下丘脑和垂体中测量多肽的表达 中枢性白介素1(IL1)刺激后。海马区皮质类固醇 结合也将在中心IL1之后进行测量。一套额外的 动物将被给予束缚应激；行为和分子 杏仁核CRF系统的测量将与杏仁核一起进行。 磷酸化CERB水平。老鼠模型的开发也将启动。 考虑到这一物种可以接受转基因操作。而当 在进行基础研究时，临床导师将监督 研究计划，并为申请人提供临床教程 精神神经免疫学和晚年抑郁症。此外，他们还将 为申请者提供指导，以应用分子研究结果 对人类群体的研究。完成5年计划的目标是 使申请者成为一名独立的研究人员，能够整合分子 神经内分泌生理学研究与临床老年精神病学 研究。

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.