Early Life Experience Shapes Visceral Circuits

早期生活经历塑造内脏回路

• 批准号: 8019103
• 负责人: Linda M Rinaman
• 金额: $ 33.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-20 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019103
• 关键词: Acute; Address; Adult; Affect; Animal Experimentation; Anxiety; Attention; Behavior; Behavioral; Biological Assay; Blood specimen; Brain; Brain Stem; CRH gene; Caregivers; Caring; Corticosterone; Data; Development; Disease; Dopamine-beta-monooxygenase; Emotional; Emotional Stress; Emotions; Epigenetic Process; Event; Exposure to; Female; Fixatives; Fright; Growth and Development function; Health; Hormonal; Human; Hypothalamic structure; Individual; Infant; Label; Laboratory Rat; Learning; Lentivirus Vector; Life; Life Experience; Link; Lithium Chloride; Methods; Modeling; Monitor; Mothers; Motivation; Motor; Neuroanatomy; Neurons; Odors; Outcome; Pathway interactions; Physiological; Plasma; Price; Prosencephalon; Rattus; Recording of previous events; Reporting; Research; Screening procedure; Sensory; Septic Toxemia; Sex Characteristics; Sexual Maturation; Shapes; Signal Transduction; Stimulus; Stress; Stressful Event; Suid Herpesvirus 1; Testing; Variant; Visceral; Weaning; Work; acute stress; animal facility; comparative; density; developmental plasticity; early experience; enhanced green fluorescent protein; experience; insight; male; maternal separation; neural circuit; neuroregulation; noradrenergic; offspring; postnatal; promoter; pup; relating to nervous system; research study; response; restraint; restraint stress; sensory feedback; sex; showing emotion; stressor; tissue fixing; young adult

DESCRIPTION (provided by applicant): 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. Interactions between infants and their mother (or primary caregiver) are critical for normal growth and development, and perturbations can disrupt physiological and behavioral functions in the offspring. The proposed research will use anatomical and physiological methods in rats to test the hypothesis that the influence of early life events on later responses to stress and emotional events is linked to developmental plasticity of circuits that provide visceral sensory feedback to the brain and generate emotional expression.

描述（由申请人提供）：早期的生活经历可以改变成人的情绪和压力反应能力，但只有有限的研究探讨了经历如何塑造中枢神经回路的发展。我们预测，对早期生活经历的操纵将改变中枢内脏回路的功能组织，而神经解剖学的改变将与对压力事件的行为、生理和神经反应的改变相对应。拟议的研究将通过对成年雄性和雌性大鼠进行实验来测试这一预测，这些大鼠的发育史是在产后前两周内每天与母体分离 15 分钟 (MS15) 或 3 小时 (MS180)。未分离的（MS0）大鼠将作为对照。成年后，所有大鼠都将在高架十字迷宫中进行行为差异筛查，并收集血样以记录约束应激引起的血浆皮质酮偏移。目标 1 和 2 的后续实验将在经过行为和激素筛选的成年大鼠中进行。目标 1 实验将检验以下假设：早期孕产妇护理（通过 MS15 和 MS180 操纵）与性相互作用，以差异性地改变中枢内脏回路的解剖特征。伪狂犬病病毒的逆行跨神经元转运将用于探测具有不同发育史的大鼠中枢自主神经回路的差异。在第二个实验中，将检查去甲肾上腺素能（NA）感觉通路的经验依赖性改变。为此，将在多巴胺β羟化酶启动子控制下表达增强型绿色荧光蛋白的独特慢病毒载体显微注射到尾髓中，以标记转染的NA神经元的轴突，投射到下丘脑和边缘前脑。目标 2 实验将检验这一假设，即早期产妇护理与性相互作用，以差异性地改变压力源诱导的中枢内脏回路节点中的神经 Fos 激活。在约束、LiCl 处理、捕食者气味暴露或匹配对照处理后，将用固定剂灌注大鼠，以分析刺激诱导的髓质 NA 神经元及其中央投射域中的 Fos 表达。 NA 末端免疫标记密度和 CRF/CRH 标记也将被量化，以确定性别和/或 MS 组差异是否相互作用。将在筛查测试中的行为和激素反应背景下对数据进行分析和解释，重点关注产后早期经历和性对解剖和生理结果的预测影响。拟议的工作将增进我们对早期孕产妇护理如何改变男性和女性中枢内脏回路的发育轨迹的理解，并将提供关于早期经历对成人情绪和压力反应的影响的新见解。婴儿与其母亲（或主要照顾者）之间的互动对于正常生长和发育至关重要，而干扰可能会破坏后代的生理和行为功能。拟议的研究将使用大鼠的解剖学和生理学方法来检验这一假设，即早期生活事件对以后对压力和情绪事件的反应的影响与向大脑提供内脏感觉反馈并产生情绪表达的回路的发育可塑性有关。