Early Life Experience Shapes Visceral Circuits

项目摘要/摘要 早期生活经历可以改变成人的情绪性和压力反应，但只有有限的研究 研究了经验如何塑造中枢神经回路的发展。我们预测，操纵 早期的生活经历会改变中枢内脏回路的功能组织，而这种改变 神经解剖学将与对应激事件改变的行为、生理和神经反应相对应。 拟议的研究将通过在成年雄性和雌性大鼠身上进行实验来验证这一预测。 曾短暂处理过每天15分钟(MS15)或3分钟的母婴分离的发展史 出生后前两周的心率(MS180)。未分离的(MS0)大鼠将作为对照。在年轻的时候 成年后，所有大鼠将在高架加迷宫中进行行为差异筛查，并将采集血样 收集来记录束缚应激引起的血浆皮质酮的漂移。随后的实验 在目标1和目标2中，将在行为和激素筛查的成年大鼠中进行试验。目标1实验将 测试早期产妇护理(通过MS15和MS180操纵)与性相互作用的假设 不同地改变中枢内脏环路的解剖特征。逆行跨神经元运输 伪狂犬病病毒将被用来探测不同疾病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(NA)的经验依赖性改变 我们将对感觉通路进行检查。为此，一种独特的慢病毒载体表达了增强的绿色 在多巴胺β羟基酶启动子控制下的荧光蛋白将被显微注射到 尾侧延髓标记转基因NA神经元投射到下丘脑和 边缘前脑。目的2实验将检验这一假设，即早期产妇护理与性行为相互作用 差异改变应激源诱导的中枢内脏回路节点的神经Fos激活。大鼠将被灌流 使用约束后的固定剂、氯化锂处理、捕食者气味暴露或匹配对照处理进行分析 刺激诱导的Fos在延髓核神经元及其中央投射野的表达。NA终端 免疫标记密度和CRF/CRH标记也将被量化，以确定性别和/或多发性硬化 群体差异是相互影响的。将在行为和荷尔蒙的背景下分析和解释数据 筛查测试中的反应，注意早期产后经历和性别的预测效果 关于解剖学和生理学的结果。拟议的工作将促进我们对多早 产妇护理可以改变男性和女性中枢内脏回路的发育轨迹，并将 提供有关早期经历对成人情绪性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.