Mechanisms of Trace Fear Conditioning in the Developing Rat

描述(由申请人提供)：这份R21探索性拨款申请将研究学习个体发生学中一个被很大程度忽视且鲜为人知的原则-习得与表达--这可能会对海马体依赖记忆的发展和神经基础产生新的见解。关于个体发育过程中延迟恐惧条件反射的习得和表达的研究，已经对杏仁核和特定的传出通路如何合作产生获得性恐惧产生了新的和意想不到的见解。然而，其他关于其他类型学习的发展研究表明，习得首先发生，这种学习的表达出现在发展的后期。为了探索在海马体依赖学习的情况下这两种可能性，特拉华大学的Mark Stanton博士和Jeff Rosen博士以及威廉与玛丽学院的Pam Hunt博士将使用行为、分子和神经药理学方法研究发育中大鼠微量恐惧条件反射的获得和表达。在目标1中，Hunt实验室的两项研究将探索习得与学习表达在大鼠出生后23天至28天之间的个体发育出现痕迹条件作用中的作用。在目标2中，将在罗森实验室对在目标1中进行行为测试的大鼠的大脑进行即刻早期基因表达分析，以探索发育差异在海马区和杏仁核神经活动和/或可塑性在痕量恐惧条件反射个体发生中的作用。在目标3中，斯坦顿实验室的两个实验将确定背侧海马区NMDA受体介导的神经可塑性在PD23-28大鼠习得性与视觉痕迹条件反射表达的个体发育中的作用。这个项目具有创新性，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海马体依赖学习的习得和表达的项目。如果成功，它将产生新的和重要的见解，将在后续的R01应用中进行更彻底的探索。该项目还具有重要意义，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，对于研究发育期酒精暴露的不良认知影响，微量恐惧条件反射是一个特别敏感的结果指标。然而，对这些影响的神经机制的理解因缺乏关于大脑-行为关系的信息而受到阻碍，这些关系在这一发育阶段调节痕迹条件作用。这个R21项目试图填补这一空白。最后，该项目将建立一个新的多研究者合作，具有推动学习的发展神经生物学中的这些和其他重要问题的强大潜力。 公共卫生相关性：拟议的项目将通过建立创新的新方法来更好地理解海马体依赖记忆的个体发生，并确定习得过程与表达过程是否有助于相对较晚的痕迹恐惧条件反射的出现，从而影响公共健康。拟议的项目将促进基础动物研究和临床实践，针对涉及海马体异常成熟的广泛发育神经行为障碍。通过阐明习得与认知功能表达的发展时机，拟议的研究可能会导致对认知发展受损的评估和干预在个体发育(当信息获得时)比目前的典型做法(等到信息表达时才到发育阶段)更早发生。最后，这一应用程序将通过将其翻译应用于正在进行的胎儿酒精谱系障碍(FASD)啮齿动物模型的研究来促进公共卫生。如果成功，这将有助于这项正在进行的研究确定酒精损害认知发展以及营养或经验干预改善行为结果的发育和神经机制。

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.