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）：此 R21 探索性资助申请将研究一个很大程度上被忽视且知之甚少的学习个体发育原理（习得与表达），这可能会对海马体的发育和神经基础产生新的见解依赖记忆。对个体发育过程中延迟恐惧调节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且意想不到的见解。然而，其他类型学习的发展研究表明，习得首先发生，而这种学习的表达在发展过程中出现得较晚。为了探索海马体依赖性学习的这两种可能性，博士。特拉华大学的马克·斯坦顿和杰夫·罗森；威廉玛丽学院的 Pam Hunt 博士将使用行为、分子和神经药理学方法来研究发育中的老鼠的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学习习得与表达在大鼠出生后第 23 天和第 28 天个体发育出现痕迹调节中的作用。在目标 2 中，罗森实验室将对目标 1 中进行行为测试的大鼠大脑进行立即早期基因表达测定，以探索海马体和杏仁核神经活动和/或可塑性的发育差异在个体发育中的作用。追踪恐惧调节。在目标 3 中，Stanton 实验室的两项实验将确定背侧海马 NMDA 受体介导的神经可塑性对 PD23-28 大鼠视觉痕迹调节的个体发育与表达的贡献。该项目具有创新性，因为它将是第一个使用综合的多学科方法来检查个体发育过程中海马依赖学习的习得与表达的项目。如果成功，它将产生新颖且重要的见解，并将在后续的 R01 应用中更彻底地追求这些见解。该项目还具有重要意义，因为它将推进涉及海马成熟异常的发育障碍的研究。例如，亨特博士的实验室表明，微量恐惧调节是研究发育性酒精暴露的不良认知影响的一种特别敏感的结果测量。然而，由于缺乏关于这一发育时期调节痕迹调节的大脑行为关系的信息，阻碍了对这些效应的神经机制的理解。 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，该合作具有巨大的潜力，可以推进学习的发展神经生物学中的这些和其他重要问题。 公共健康相关性：拟议的项目将通过建立创新的新方法来更好地理解海马依赖性记忆的个体发育，并确定习得过程与表达过程是否有助于相对较晚出现的痕迹恐惧条件反射，从而影响公共健康。拟议的项目将推进针对涉及海马成熟异常的广泛发育神经行为障碍的基础动物研究和临床实践。通过阐明认知功能的获取与表达的发展时间，拟议的研究可能会导致对认知发展受损的评估和干预发生在个体发育（获取信息时），而不是典型的当前实践（等到信息获取时）。信息表达的发展阶段）。最后，该应用程序将通过其转化应用到正在进行的胎儿酒精谱系障碍（FASD）啮齿动物模型研究中来促进公共健康。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，以及营养或体验干预改善行为结果的机制。