Mechanisms of Trace Fear Conditioning in the Developing Rat

发育中大鼠的微量恐惧调节机制

• 批准号: 8206412
• 负责人: PAMELA S HUNT
• 金额: $ 22.45万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8206412
• 关键词: Accounting; Address; Adolescent; Adult; Affect; Age; Alcohols; Amygdaloid structure; Animal Experimentation; Animals; Applications Grants; Area; Behavior; Behavioral; Biological Assay; Brain; Cognitive; Collaborations; Delaware; Development; Dorsal; Efferent Pathways; Exploratory/Developmental Grant; FOS gene; Failure; Fetal Alcohol Spectrum Disorder; Fright; Future; Gene Expression; Growth; Hippocampus (Brain); Human; Immediate-Early Genes; Infusion procedures; Intervention; Laboratories; Learning; Literature; Measures; Mediating; Memory; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Neurobiology; Neuronal Plasticity; Nutritional; Outcome; Outcome Measure; Performance; Pharmaceutical Preparations; Process; Proteinase 3; Public Health; Rattus; Research; Research Personnel; Risk; Rodent Model; Role; Savings; Staging; System; Testing; Time; Training; Universities; Visual; Weaning; Work; alcohol exposure; base; brain behavior; brain tissue; clinical practice; cognitive function; college; conditioned fear; conditioning; design; developmental disease; developmental neurobiology; improved; innovation; insight; interdisciplinary approach; interest; neglect; neurobehavioral disorder; neurobiological mechanism; neurodevelopment; neuromechanism; novel; novel strategies; postnatal; prevent; relating to nervous system; research study; response; visual stimulus

DESCRIPTION (provided by applicant): This R21 exploratory grant application will study a largely neglected and poorly understood principle of the ontogeny of learning---acquisition vs. expression---that will likely yield new insights into the development and neural basis of hippocampus-dependent memory. Research on acquisition vs. expression of delay fear conditioning during ontogeny has yielded novel and unanticipated insights concerning how the amygdala and specific efferent pathways cooperate to generate learned fear. However, other developmental research with other types of learning indicates that acquisition occurs first and expression of this learning emerges later in development. To explore these two possibilities in the case of hippocampus-dependent learning, Drs. Mark Stanton and Jeff Rosen at the University of Delaware; and Dr. Pam Hunt at the College of William and Mary will use behavioral, molecular and neuropharmacological approaches to study acquisition vs. expression of trace fear conditioning in developing rats. In Aim 1, two studies in the Hunt laboratory will explore the role of acquisition vs. expression of learning in the ontogenetic emergence trace conditioning between postnatal day (PD) 23 and PD28 in the rat. In Aim 2, immediate-early-gene expression assays will be performed in the Rosen laboratory on the brains of rats tested behaviorally in Aim 1 to explore the role of developmental differences in neural activity and/or plasticity in hippocampus and amygdala in the ontogeny of trace fear conditioning. In Aim 3, two experiments in the Stanton laboratory will determine the contribution of NMDA- receptor-mediated neural plasticity in dorsal hippocampus to the ontogeny of acquisition vs. expression of visual trace conditioning in PD23-28 rats. This project is innovative because it will be the first to examine acquisition vs. expression of hippocampus-dependent learning during ontogeny using an integrated, multidisciplinary approach. If successful, it will yield novel and important insights that would be pursued more thoroughly in subsequent R01 applications. The project is also significant because it will advance the study of developmental disorders involving aberrant maturation of the hippocampus. For example, Dr. Hunt's laboratory has shown that trace fear conditioning is an especially sensitive outcome measure for studying adverse cognitive effects of developmental alcohol exposure. However, understanding of the neural mechanisms of these effects is hampered by a lack of information on brain-behavior relationships mediating trace conditioning during this period of development. This R21 project seeks to fill that gap. Finally, this project will establish a new multi-investigator collaboration that has strong potential to advance these and other important issues in the developmental neurobiology of learning. PUBLIC HEALTH RELEVANCE: The proposed project will impact public health by establishing innovative new approaches to better understand the ontogeny of hippocampus-dependent memory, and determining whether processes of acquisition vs. expression contribute to the relatively late emergence of trace fear conditioning. The proposed project will advance both basic animal research and clinical practice directed at a broad range of developmental neurobehavioral disorders involving abnormal maturation of the hippocampus. By elucidating the developmental timing of acquisition vs. expression of cognitive function, the proposed research could cause assessment of, and interventions for, impaired cognitive development to occur earlier in ontogeny (when information is acquired) than is typical of current practices (which wait until stages of development when information is expressed). Finally, this application will advance public health via its translational application to ongoing research on rodent models of Fetal Alcohol Spectrum Disorder (FASD). If successful, it will help this ongoing research identify the developmental and neural mechanisms through which alcohol impairs cognitive development and through which nutritional or experiential interventions improve behavioral outcome.

描述（由申请人提供）：这个R21探索性资助申请将研究学习的个体发育的一个基本上被忽视和理解不足的原则-获取与表达-这可能会产生新的见解，发展和神经基础依赖于校园的记忆。个体发育过程中延迟恐惧条件反射的获得与表达的研究已经产生了关于杏仁核和特定传出通路如何合作产生习得性恐惧的新颖和意想不到的见解。然而，对其他类型学习的其他发展研究表明，习得首先发生，这种学习的表达在发育后期出现。为了探索这两种可能性，特拉华州大学的马克·斯坦顿和杰夫·罗森博士以及威廉和玛丽学院的帕姆·亨特博士将使用行为、分子和神经药理学方法来研究发育中大鼠微量恐惧条件反射的获得与表达。在目标1中，Hunt实验室的两项研究将探讨大鼠在出生后第23天（PD）和PD 28天之间的个体发育出现痕迹条件反射中学习的获得与表达的作用。在目标2中，将在罗森实验室对目标1中进行行为测试的大鼠的大脑进行立即早期基因表达测定，以探索海马和杏仁核中神经活动和/或可塑性的发育差异在微量恐惧条件反射个体发育中的作用。在目标3中，Stanton实验室的两个实验将确定背海马中NMDA受体介导的神经可塑性对PD 23 -28大鼠中视觉痕迹条件反射的获得与表达的个体发育的贡献。这个项目是创新的，因为它将是第一个使用综合的，多学科的方法来研究个体发育过程中依赖于校园学习的获取与表达。如果成功，它将产生新的和重要的见解，将在随后的R 01应用程序中更彻底地追求。该项目也很重要，因为它将推进涉及海马体异常成熟的发育障碍的研究。例如，亨特博士的实验室已经表明，微量恐惧条件反射是一种特别敏感的结果测量方法，用于研究酒精暴露对发育的不良认知影响。然而，这些影响的神经机制的理解是阻碍了在这一时期的发展过程中，大脑行为的关系介导的痕迹条件反射的信息缺乏。R21项目旨在填补这一空白。最后，该项目将建立一个新的多研究者合作，具有强大的潜力，以推进这些和其他重要问题的发展神经生物学的学习。 公共卫生关系：拟议的项目将通过建立创新的新方法来更好地理解依赖于校园记忆的个体发育，并确定获取与表达的过程是否有助于相对较晚出现的痕迹恐惧条件反射，从而影响公共卫生。拟议的项目将推进基础动物研究和临床实践，针对广泛的发育性神经行为障碍，涉及海马体的异常成熟。通过阐明认知功能的获取与表达的发育时间，拟议的研究可能会导致对认知发育受损的评估和干预在个体发育（当获取信息时）中发生，而不是典型的当前实践（等到信息表达时的发育阶段）。最后，该应用程序将通过其转化应用于正在进行的胎儿酒精谱系障碍（FASD）啮齿动物模型研究来促进公共卫生。如果成功，它将有助于这项正在进行的研究确定酒精损害认知发展的发育和神经机制，以及营养或经验干预改善行为结果的机制。