Alcohol and Stress: Interactive Effects

酒精和压力：互动效应

• 批准号: 8277035
• 负责人: JOANNE WEINBERG
• 金额: $ 23.71万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277035
• 关键词: Adrenal Glands; Adrenalectomy; Adult; Adult Children; Adverse effects; Alcohols; Animal Model; Animals; Antidepressive Agents; Anxiety; Anxiety Disorders; Area; Behavior; Behavioral; Brain; Child; Chronic; Circadian Rhythms; Clinical; Cognitive; Corticosterone; Data; Development; Disease susceptibility; Emotional Stress; Event; Exhibits; Exposure to; Feedback; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Gonadal Hormones; Gonadal Steroid Hormones; Health; Hormonal; Hydrocortisone; Hypothalamic structure; Incidence; Individual; Intervention; Laboratories; Life; Link; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Modeling; Neurobiology; Outcome; Ovariectomy; Pattern; Personal Satisfaction; Pituitary Gland; Problem behavior; Regulation; Research; Role; Serotonin; Sex Characteristics; Stress; System; Testing; base; biological adaptation to stress; depressive symptoms; disability; emerging adult; fetal; fetal programming; hypothalamic pituitary gonadal axis; hypothalamic-pituitary-adrenal axis; male; neurobehavioral; neuropsychological; novel; novel therapeutic intervention; offspring; pre-clinical; pregnant; response; sex; stressor

DESCRIPTION (provided by applicant): Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive, neuropsychological and neurobehavioral problems that range from mild to severe. Moreover, secondary disabilities in a number of life domains are common, including a high incidence of depression and anxiety disorders. Hypothalamic- pituitary-adrenal (HPA) dysregulation is a common finding in major depression. Furthermore, there is a strong relationship between depression in adulthood and adverse early life events. Consistent with these findings, brain areas implicated in depression overlap with areas that mediate the stress response, with the HPA axis a key player in both. We have shown that prenatal alcohol exposure (PAE) reprograms the fetal HPA axis such that HPA tone is increased throughout life. PAE offspring are typically hyperresponsive to stressors, and show both increased HPA drive and deficits in feedback regulation. Furthermore, interactions between the HPA axis and both the gonadal and serotonergic systems are altered by PAE. This pattern of dysregulation parallels in many ways what is observed in depression. The present proposal will utilize our well-established animal model of PAE to examine the links among PAE, stress system abnormalities, the gonadal and serotonergic systems and depression. In the context of the stress-diathesis model, we will test the hypothesis that fetal programming of HPA activity by PAE permanently sensitizes neuroadaptive mechanisms that mediate responses to stress, resulting in hyper- reactivity to subsequent, even mild, stressful life events. Ultimately, repeated stress exposure results in a maladaptive cascade of events and increased vulnerability to depression and anxiety. Our Preliminary Studies demonstrate sex-dependent increases in depressive symptomatology in PAE animals following exposure to chronic mild stress (CMS) in adulthood. The proposed studies will extend these finding in important and novel directions. Our Specific Aims are to investigate: 1) the role of the maternal hormonal milieu in programming fetal HPA activity, sensitizing the offspring HPA axis, and mediating increased vulnerability to adverse effects of stress on offspring HPA, brain and behavioural outcomes; 2) the role of HPA dysregulation in adult PAE males and females in mediating increased vulnerability to adverse effects of stress on HPA, brain and behavioural outcomes, and the role of the gonadal hormones in mediating the sexually dimorphic effects of PAE and stress that are observed; and 3) whether antidepressant treatment can reverse or alleviate the adverse effects of stress on HPA, brain and behavioural outcomes in PAE offspring. The proposed studies will elucidate mechanisms mediating the link between PAE and increased vulnerability to depression and anxiety disorders in children with FASD, and have important implications for the development of novel therapeutic interventions. PUBLIC HEALTH RELEVANCE Children with Fetal Alcohol Spectrum Disorder (FASD) exhibit cognitive, neuropsychological and behavioral problems, as well as numerous secondary disabilities, the most prominent being mental illnesses such as depression. The present research utilizes our well established animal model of prenatal alcohol exposure to examine the role of stress system abnormalities in mediating this increased incidence of depression. The data from these studies will significantly increase our understanding of the mechanisms underlying the long term and far reaching consequences of prenatal alcohol exposure on health and well-being, and will have important implications for the development of novel therapeutic interventions for depression in individuals with FASD.

描述（由申请人提供）：患有胎儿酒精谱系障碍（FASD）的儿童表现出轻度至重度的认知、神经心理和神经行为问题。此外，在一些生活领域，继发性残疾很常见，包括抑郁症和焦虑症的高发率。下丘脑-垂体-肾上腺（HPA）失调是抑郁症的常见表现。此外，成年期抑郁症与早期不良生活事件之间存在密切关系。与这些发现一致，与抑郁症有关的大脑区域与介导压力反应的区域重叠，HPA轴在两者中发挥着关键作用。我们已经表明，产前酒精暴露（PAE）重新编程胎儿HPA轴，使HPA张力增加整个生命。PAE后代通常对压力源反应过度，并且显示出增加的HPA驱动和反馈调节的缺陷。此外，HPA轴与性腺和肾上腺素能系统之间的相互作用被PAE改变。这种失调模式在许多方面与抑郁症中观察到的相似。目前的建议将利用我们完善的PAE动物模型来研究PAE，应激系统异常，性腺和肾上腺素能系统和抑郁症之间的联系。在应激素质模型的背景下，我们将检验以下假设：PAE对HPA活性的胎儿编程永久地使介导对应激的反应的神经适应机制敏感，导致对随后的、甚至是轻微的应激性生活事件的高反应性。最终，反复的压力暴露会导致一系列适应不良的事件，并增加对抑郁和焦虑的脆弱性。我们的初步研究表明，在成年期暴露于慢性轻度应激（CMS）后，PAE动物的抑郁性抑郁症呈性别依赖性增加。拟议的研究将在重要和新颖的方向扩展这些发现。我们的具体目标是调查：1）母体激素环境在编程胎儿HPA活性，使后代HPA轴敏感，以及介导对后代HPA，大脑和行为结果的应激不利影响的脆弱性增加中的作用; 2）成年PAE男性和女性中HPA失调在介导对HPA、大脑和行为结果的压力不利影响的脆弱性增加中的作用，以及性腺激素在介导所观察到的PAE和应激的性二态效应中的作用;以及3）抗抑郁药治疗是否可以逆转或减轻应激对PAE后代的HPA、大脑和行为结果的不利影响。拟议的研究将阐明调节PAE与FASD儿童抑郁和焦虑障碍易感性增加之间联系的机制，并对开发新型治疗干预措施具有重要意义。 患有胎儿酒精谱系障碍（FASD）的儿童表现出认知、神经心理和行为问题，以及许多继发性残疾，最突出的是抑郁症等精神疾病。本研究利用我们建立的产前酒精暴露的动物模型来研究应激系统异常在介导抑郁症发病率增加中的作用。这些研究的数据将显著增加我们对产前酒精暴露对健康和福祉的长期和深远影响的机制的理解，并将对FASD患者抑郁症的新型治疗干预措施的开发产生重要影响。