Alcohol and Stress: Interactive Effects

酒精和压力：互动效应

• 批准号: 9493350
• 负责人: JOANNE WEINBERG
• 金额: $ 26.32万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9493350
• 关键词: Acute; Address; Adolescence; Adrenalectomy; Adult; Adult Children; Adverse effects; Alcohols; Animal Model; Animals; Anti-inflammatory; Antidepressive Agents; Anxiety; Anxiety Disorders; Attenuated; Award; Behavior; Behavioral; Biological; Bipolar Disorder; Brain; Child; Chronic; Data; Development; Disease susceptibility; Elderly; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Gonadal Hormones; Grant; Health; Hormonal; Hormones; Hypothalamic structure; Immune; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Instruction; Life; Life Stress; Link; Long-Term Effects; Major Depressive Disorder; Mediating; Mental Depression; Modeling; Neuroimmune; Neurosecretory Systems; Organism; Outcome; Personal Satisfaction; Pituitary Gland; Regulation; Research; Risk Factors; Role; Serotonergic System; Serotonin; Stress; System; Testing; anxiety-like behavior; behavior test; behavioral outcome; biological adaptation to stress; depressive symptoms; fetal programming; male; neuroinflammation; novel therapeutic intervention; offspring; stress related disorder; stressor

Depression is often described as a stress-related disorder, as it often occurs in the context of exposure to some form of stress. Indeed, alterations in HPA activity and regulation are one of the most consistently described biological abnormalities in depression and bipolar disorder. Stress can cause remodelling and microdamage in the brain, and can stimulate neuroinflammation. Moreover, significant risk factors for major depressive disorder are associated with increased inflammation; in turn, inflammatory mediators can induce depressive symptoms. In most cases, short-term stress-induced neuroinflammatory activation resolves, and the organism is then resilient in the face of later-life challenges. In the case of an organism with pre-existing vulnerability, such as occurs with PAE, short-term neuroinflammation may fail to resolve, and can progress to a more chronic condition, leaving the organism vulnerable to later life challenge. The present proposal will test the hypothesis that fetal programming of HPA activity by PAE results in altered neuroendocrine- neuroimmune interactions, giving rise to a sensitized, vulnerable organism, with an increased pro- inflammatory bias, that is predisposed to increased responsiveness to stressors or immune challenges later in life, resulting in increased vulnerability to stress-related disorders such as depression and anxiety. This hypothesis will be tested in three Specific Aims: 1) To determine the immediate or short-term effects of PAE and later life stress on depressive-/anxiety-like behavior and behavior mediated by the PFC, as well as markers of stress and neuroimmune function; 2) To examine the long-term effects of PAE and stress in adulthood or adolescence on depressive-/anxiety-like behavior and behavior mediated by the PFC, as well as markers of stress and neuroimmune function; and 3) To investigate the efficacy of antidepressant and anti-inflammatory treatments, separately or in combination, in attenuating or normalizing the adverse effects of PAE and later life stress and/or immune challenges on behavioral, brain, HPA and neuroimmune outcomes. Together, the data from these studies will have important implications for the development of novel therapeutic interventions for depression in individuals with FASD. RELEVANCE (See instructions): The present research utilizes our well-established animal model of prenatal alcohol exposure to examine the role of stress and neuroimmune abnormalities in mediating the increased incidence of depression observed in children with FASD. Our data will significantly increase our understanding of the mechanisms underlying the long-term 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.

抑郁症通常被描述为一种与压力有关的疾病，因为它经常发生在暴露于 某种形式的压力事实上，HPA活性和调节的改变是最一致的 描述了抑郁症和双相情感障碍的生物学异常。压力会导致重塑， 大脑中的微损伤，并能刺激神经炎症。此外，重大风险因素 抑郁症与炎症增加有关;反过来，炎症介质可以诱导 抑郁症状。在大多数情况下，短期应激诱导的神经炎症激活消退， 这样，生物体在面对晚年的挑战时就有了弹性。如果一个生物体预先存在 脆弱性，如发生与PAE，短期神经炎症可能无法解决，并可能进展 更慢性的疾病，使机体在以后的生活挑战中变得脆弱。本提案将 测试假设，胎儿编程的HPA活动的PAE的结果改变神经内分泌- 神经免疫相互作用，产生一个敏感的，脆弱的生物体，增加亲- 炎症偏向，即倾向于增加对应激源或免疫挑战的反应， 生活中，导致更容易受到与压力有关的疾病，如抑郁和焦虑。这 将在三个特定目标中检验假设：1）确定PAE的即时或短期影响 和以后的生活压力对抑郁/焦虑样行为和PFC介导的行为的影响，以及 应激和神经免疫功能的标志物; 2）检查PAE和应激对 成年期或青春期抑郁/焦虑样行为和PFC介导的行为，以及 作为应激和神经免疫功能的标志物; 3）研究抗抑郁药和 单独或组合的抗炎治疗，以减轻或使不良反应正常化 PAE和以后的生活压力和/或免疫挑战对行为，大脑，HPA和神经免疫 结果。总之，这些研究的数据将对开发 FASD患者抑郁症的新型治疗干预 相关性（参见说明）： 本研究利用我们成熟的产前酒精暴露动物模型， 压力和神经免疫异常在介导抑郁症发病率增加中的作用 在患有FASD的儿童中。我们的数据将大大增加我们对潜在机制的理解 产前酒精暴露对健康和福祉的长期后果，并将有重要的 对FASD患者抑郁症的新型治疗干预措施的发展具有重要意义。

项目成果

Prenatal alcohol exposure alters gene expression in the rat brain: Experimental design and bioinformatic analysis of microarray data.

产前酒精暴露改变大鼠大脑中的基因表达：微阵列数据的实验设计和生物信息学分析。

• DOI: 10.1016/j.dib.2015.05.007
• 发表时间: 2015
• 期刊: Data in brief
• 影响因子: 1.2
• 作者: Lussier,AlexandreA;Stepien,KatarzynaA;Weinberg,Joanne;Kobor,MichaelS
• 通讯作者: Kobor,MichaelS

Neonatal handling: an overview of the positive and negative effects.

• DOI: 10.1002/dev.21241
• 发表时间: 2014-12
• 期刊: Developmental psychobiology
• 影响因子: 2.2
• 作者: Raineki C;Lucion AB;Weinberg J
• 通讯作者: Weinberg J

Prenatal alcohol exposure alters steady-state and activated gene expression in the adult rat brain.

产前酒精暴露会改变成年大鼠大脑中稳态和激活的基因表达。

• DOI: 10.1111/acer.12622
• 发表时间: 2015
• 期刊: Alcoholism, clinical and experimental research
• 作者: Lussier,AlexandreA;Stepien,KatarzynaA;Neumann,SarahM;Pavlidis,Paul;Kobor,MichaelS;Weinberg,Joanne
• 通讯作者: Weinberg,Joanne

Prenatal Alcohol Exposure and Pair Feeding Differentially Impact Puberty and Reproductive Development in Female Rats: Role of the Kisspeptin System.

产前酒精暴露和配对喂养对雌性大鼠青春期和生殖发育的不同影响：Kisspeptin 系统的作用。

• DOI: 10.1111/acer.13233
• 发表时间: 2016
• 期刊: Alcoholism, clinical and experimental research
• 作者: Sliwowska,JoannaHelena;Comeau,WendyL;Bodnar,TamaraS;Ellis,Linda;Weinberg,Joanne
• 通讯作者: Weinberg,Joanne

Impact of adolescent stress on the expression of stress-related receptors in the hippocampus of animals exposed to alcohol prenatally.

• DOI: 10.1002/hipo.22823
• 发表时间: 2018-03
• 期刊: Hippocampus
• 影响因子: 3.5
• 作者: Raineki C;Ellis L;Weinberg J
• 通讯作者: Weinberg J