Early Life Experience Shapes Visceral Circuits

项目总结/摘要 早期的生活经历可以改变成年人的情绪和压力反应，但只有有限的研究表明， 研究了经验如何塑造中枢神经回路的发展。我们预测， 早期的生活经历会改变中枢内脏回路的功能组织， 神经解剖学将与对压力事件的行为、生理和神经反应的改变相对应。 这项拟议中的研究将通过在成年雄性和雌性大鼠中进行实验来验证这一预测， 每日母体分离15分钟（MS 15）或3分钟（MS 15）的短暂处理的发育史 hr（MS180）。未分离（MS 0）大鼠作为对照。一样年轻 在成年后，将筛选所有大鼠在高架十字迷宫中的行为差异，并将血样 收集以记录束缚应激诱发的血浆皮质酮波动。随后的实验 将在行为和行为筛选的成年大鼠中进行。目标1实验将 检验早期孕产妇护理（通过MS 15和MS 180操作）与性别相互作用的假设， 差异地改变中枢内脏回路的解剖学特征。逆行跨神经元转运 伪狂犬病病毒将被用于探测在不同的大鼠中枢自主神经回路的差异， 发展史在第二个实验中，去甲肾上腺素能（NA） 将检查感觉通路。为此，一个独特的慢病毒载体，表达增强的绿色 在多巴胺β羟化酶启动子控制下的荧光蛋白将被显微注射到 尾侧髓质标记投射到下丘脑的转染NA神经元的轴突主干， 边缘前脑目的2实验将检验这一假设，即早期孕产妇保健与性别相互作用， 差异改变应激诱导的神经Fos激活中枢内脏电路节点。将对大鼠进行灌注 在约束、LiCl处理、捕食者气味暴露或匹配的对照处理后使用固定剂进行分析 在延髓NA神经元及其中央投射区，刺激诱导Fos表达。NA末端 免疫标记密度和CRF/CRH标记也将定量，以确定性别和/或MS 群体差异相互作用。数据将在行为和激素的背景下进行分析和解释。 筛查试验中的反应，注意产后早期经历和性别的预测影响 解剖学和生理学的结果。拟议的工作将促进我们了解如何尽早 母亲的照顾可以改变男性和女性中枢内脏回路的发育轨迹， 提供了关于早期经验对成人情绪和压力反应的影响的新见解。

Project Summary/Abstract Early life experience can alter adult emotionality and stress responsiveness, but only limited research has examined how experience shapes the development of central neural circuits. We predict that manipulation of early life experience will alter the functional organization of central visceral circuits, and that altered neuroanatomy will correspond with altered behavioral, physiological, and neural responses to stressful events. The proposed research will test this prediction by performing experiments in adult male and female rats with a developmental history of having been handled briefly for daily maternal separation of either 15 min (MS15) or 3 hr (MS180) during the first two postnatal weeks. Non-separated (MS0) rats will serve as controls. As young adults, all rats will be screened for behavioral differences in the elevated plus maze, and blood samples will be collected to document restraint stress-evoked excursions in plasma corticosterone. Subsequent experiments in Aims 1 and 2 will be performed in behaviorally- and hormonally-screened adult rats. Aim 1 experiments will test the hypothesis that early maternal care (manipulated via MS15 and MS180) interacts with sex to differentially alter the anatomical features of central visceral circuits. Retrograde transneuronal transport of pseudorabies virus will be used to probe for differences in central autonomic circuits in rats with different developmental histories. In the second experiment, experience-dependent alterations in noradrenergic (NA) sensory pathways will be examined. For this, a unique lentivirus vector that expresses enhanced green fluorescent protein under the control of a dopamine beta hydroxylase promoter will be microinjected into the caudal medulla to label the axonal arbors of transfected NA neurons that project to the hypothalamus and limbic forebrain. Aim 2 experiments will test the hypothesis that early maternal care interacts with sex to differentially alter stressor-induced neural Fos activation in central visceral circuit nodes. Rats will be perfused with fixative after restraint, LiCl treatment, predator odor exposure, or matched control treatment for analyses of stimulus-induced Fos expression in medullary NA neurons and in their central projection fields. NA terminal immunolabeling density and CRF/CRH labeling also will be quantified to determine whether sex and/or MS group differences interact. Data will be analyzed and interpreted within the context of behavioral and hormonal responses in the screening tests, with attention paid to predicted effects of early postnatal experience and sex on anatomical and physiological outcomes. The proposed work will advance our understanding of how early maternal care can alter the developmental trajectory of central visceral circuits in males and females, and will provide new insights regarding the impact of early experience on adult emotionality and stress responsiveness.