Neonatal Rearing and Adult Stress Reactivity in C57BL/6 Mice

C57BL/6 小鼠的新生儿饲养和成年应激反应

• 批准号: 7141516
• 负责人: DAVID B PARFITT
• 金额: $ 7.8万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141516
• 关键词: adrenocorticotropic hormone; behavior test; behavioral /social science research tag; child rearing; corticosterone; developmental neurobiology; disease /disorder model; early experience; gene expression; genetically modified animals; hormone regulation /control mechanism; laboratory mouse; mature animal; model design /development; mother child interaction; mother deprivation; neural information processing; newborn animals; psychological stressor; stimulus /response; stress; time resolved data

DESCRIPTION (provided by applicant): Experiments in this grant application are designed to build upon classic studies documenting powerful effects of early handling and maternal separation on adult stress-induced hormone secretion. There is a particularly large literature documenting how adverse neonatal experiences have major, long-term effects on the physiology and behavior of many species, including depression in humans. However, little is known about the impact of neonatal rearing environment on future, adult responses to stressful situations in the mouse. Understanding these environmental effects on mouse brain development would allow us to take advantage of powerful genetic tools available in the mouse to determine the interaction between genetic and epigenetic factors governing brain development. Because maternal separation procedures vary, research in this proposal will optimize the parameters of an early life stress model that exerts permanent long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis in adult male C57BL/6 mice. These experiments will characterize the time of day that neonatal early handling has the maximal response on adult behavior,hormone secretion, and mRNA expression, and whether the presence of littermates can buffer the effect of neonatal maternal separation on adult behavior, hormone secretion and mRNA expression in C57BL/6 mice. It is important to note that the early life stress model that alters stress hormone secretion in adult rats may not be the ideal model system for eliciting changes in adult mice. Therefore, the experiments outlined in this proposal are essential before conducting work exploring the influence of environment on genetic mutants on the C57BL/6 strain of mice. At the conclusion of the experiments in this R03 grant, we will understand the importance of critical variables during differential rearing, such as time of day and isolation from siblings, for altering maternal behavior, adult behavior, stress-induced adrenocorticotropin hormone and corticosterone secretion, and mRNA expression of regulators of the HPA axis in the C57BL/6 mouse. Finally, the basic research outlined in this proposal has clinical biomedical relevance and fulfills an aim of NIMH to decrease the burden of mental illness. Increasing evidence suggests that early adverse experience contributes to the etiology of depression, and this mouse differential rearing model could therefore be helpful in understanding how early life stressors alters neural circuitry that then influence an individual's susceptibility to depression.

描述（由申请人提供）：本拨款申请中的实验旨在建立在经典研究的基础上，这些研究记录了早期处理和母亲分离对成人压力诱导的激素分泌的强大影响。有大量文献记录了不良的新生儿经历如何对许多物种的生理和行为产生重大的长期影响，包括人类的抑郁症。然而，人们对新生儿饲养环境对小鼠未来成年小鼠应激反应的影响知之甚少。了解这些环境对小鼠大脑发育的影响将使我们能够利用小鼠中可用的强大遗传工具来确定控制大脑发育的遗传因素和表观遗传因素之间的相互作用。由于母体分离程序各不相同，本提案中的研究将优化早期生命应激模型的参数，该模型对成年雄性 C57BL/6 小鼠的下丘脑 - 垂体 - 肾上腺 (HPA) 轴产生永久的长期影响。这些实验将表征一天中新生儿早期处理对成年行为、激素分泌和 mRNA 表达具有最大反应的时间，以及同窝出生的动物的存在是否可以缓冲新生儿母体分离对成年行为、激素分泌和 mRNA 表达的影响在 C57BL/6 小鼠中。 值得注意的是，改变成年大鼠应激激素分泌的早期生活应激模型可能不是引发成年小鼠变化的理想模型系统。因此，在开展探索环境对 C57BL/6 品系小鼠基因突变体的影响的工作之前，本提案中概述的实验至关重要。在这项 R03 资助的实验结束时，我们将了解差异饲养期间关键变量的重要性，例如一天中的时间和与兄弟姐妹的隔离，对于改变母亲行为、成人行为、压力诱导的促肾上腺皮质激素和皮质酮分泌，以及 C57BL/6 小鼠 HPA 轴调节因子的 mRNA 表达。最后，该提案中概述的基础研究具有临床生物医学相关性，并实现了 NIMH 减轻精神疾病负担的目标。越来越多的证据表明，早期的不良经历会导致抑郁症的病因，因此这种小鼠差异饲养模型可能有助于了解早期生活压力源如何改变神经回路，从而影响个体对抑郁症的易感性。