Neonatal Rearing and Adult Stress Reactivity in C57BL/6 Mice

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应激诱导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、长期的影响，包括人类的抑郁症。然而，关于新生儿饲养环境对小鼠未来成年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强大的小鼠遗传工具来确定控制大脑发育的遗传和表观遗传因素之间的相互作用。由于母鼠分离过程各不相同，本研究将优化对成年雄性C57BL/6小鼠下丘脑-垂体-肾上腺（HPA）轴产生永久性长期影响的早期生活应激模型的参数。本实验将研究新生儿早期处理对C57BL/6小鼠成体行为、激素分泌和mRNA表达的最大反应时间，以及窝伴的存在是否可以缓冲新生儿母亲分离对C57BL/6小鼠成体行为、激素分泌和mRNA表达的影响。值得注意的是，改变成年大鼠应激激素分泌的早期生活压力模型可能不是引发成年小鼠变化的理想模型系统。因此，在开展环境对基因突变对小鼠C57BL/6品系的影响的研究工作之前，本提案中概述的实验是必不可少的。在本R03基金的实验结束时，我们将了解差异饲养过程中关键变量的重要性，如一天中的时间和与兄弟姐妹的隔离，对改变C57BL/6小鼠的母性行为、成体行为、应激诱导的促肾上腺皮质激素激素和皮质酮分泌以及HPA轴调节因子mRNA表达的影响。最后，本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，早期的不良经历有助于抑郁症的病因学，因此，这种小鼠差异饲养模型可能有助于理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。

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.