Individual Differences in Epigenetic Regulation of Emotional Learning

情绪学习表观遗传调节的个体差异

基本信息

批准号：
9981714
负责人：
Jonathan David Morrow
金额：
$ 46.24万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9981714
关键词：
Accounting Affect Affective Alcohol or Other Drugs use Amygdaloid structure Animal Model Automobile Driving Aversive Stimulus Axonal Transport Behavior Behavioral Brain-Derived Neurotrophic Factor Child Care Chromatin Structure Clinical Research Cocaine Complex Conditioned Reflex Cues Data Desire for food Diagnostic Disease Electrophysiology (science)Emotional Epigenetic Process Event Family Fright Gene Expression Genes Genetic Transcription Glutamates Goals Growth Factor High Prevalence Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Human Individual Individual Differences Injections Learning Long-Term Potentiation Measures Medial Mediating Mental disorders Methods Minority Mission Modification Molecular Motivation National Institute of Drug Abuse Negative Valence Neurobiology Neurons Nucleus Accumbens Outcome Measure Pathway interactions Patient-Focused Outcomes Patients Phenotype Population Positive Valence Post-Traumatic Stress Disorders Prefrontal Cortex Prevention strategy Procedures Process Rattus Regulation Relapse Research Research Project Grants Rewards Self Administration Societies Stimulus Structure Synapses Techniques Testing United States National Institutes of Health Variant Viral Vector Work addiction classical conditioning comorbidity conditioned fear conditioning design dual diagnosis effective therapy emotion regulation epigenetic regulation experience experimental study improved individual variation interest learning extinction motivated behavior neuromechanism new therapeutic target preclinical study promoter public health priorities response synaptogenesis tool trait traumatic event

项目摘要

PROJECT SUMMARY/ABSTRACT This research project focuses on identifying common neurobiological substrates that confer vulnerability both to addiction and to frequently co-occurring disorders such as post-traumatic stress disorder (PTSD). Pavlovian conditioning procedures will be used to distinguish “sign-tracking” rats that tend to attribute high levels of motivational significance to discrete predictive cues while largely ignoring context, from “goal-tracking” rats that make more use of context to appropriately modify their emotional responses. Sign-tracking individuals are more prone to both addiction- and PTSD-like behaviors than goal-trackers. The neurobiological basis of these behavioral traits will be explored by testing for differences between sign- and goal-trackers in dynamic epigenetic histone acetylation, brain-derived neurotrophic factor (BDNF) expression, and functional connectivity within key limbic circuits known to mediate motivated behavior, namely the pathway from ventral hippocampus to medial prefrontal cortex to basolateral amygdala and nucleus accumbens. Epigenetic changes and growth factor expression will also be manipulated using viral vectors to test for a causal influence on conditioned motivational responses to appetitive and aversive cues and contexts, as well as electrophysiological measures of connectivity and synaptic efficiency within the limbic pathway of interest. These experiments will test the hypothesis that decreased histone acetylation in goal-trackers relative to sign- trackers after behavioral conditioning leads to increased transcription of BDNF, which in turn is transported axonally and released onto medial prefrontal cortical targets. The BDNF then causes an increase in synaptic connectivity between the medial prefrontal cortex and its downstream targets, the basolateral amygdala and nucleus accumbens. Thus, goal-trackers are hypothesized to have an increased capacity to use contextual information, derived from hippocampal inputs and relayed through the medial prefrontal cortex, to appropriately modify subcortical responses to cues associated with emotionally salient events. This proposed R01 project is well-aligned with the missions of the NIH and NIDA, as it will help clarify neurobiological pathways to addiction and frequently co-occurring disorders, which is a significant public health priority.

项目概要/摘要该研究项目的重点是识别常见的神经生物学底物，这些底物赋予脆弱性成瘾和经常并发的疾病，如创伤后应激障碍（PTSD）。调节程序将用于区分“信号跟踪”大鼠，这些大鼠倾向于归因于高水平的离散预测线索的动机重要性，同时很大程度上忽略了上下文，来自“目标跟踪”老鼠更多地利用环境来适当地调整他们的情绪反应。比目标追踪者更容易出现成瘾和创伤后应激障碍行为。这些行为的神经生物学基础。将通过测试动态中信号跟踪器和目标跟踪器之间的差异来探索行为特征表观遗传组蛋白乙酰化、脑源性神经营养因子 (BDNF) 表达和功能已知可介导动机行为的关键边缘回路内的连接，即来自腹侧的通路海马到内侧前额皮质到基底外侧杏仁核和伏隔核的表观遗传变化。生长因子的表达也将使用病毒载体进行操纵，以测试其因果影响对食欲和厌恶线索和环境的条件性动机反应，以及感兴趣的边缘通路内连接性和突触效率的电生理测量。这些实验将检验以下假设：目标追踪器中的组蛋白乙酰化相对于信号行为调节后的追踪器导致 BDNF 转录增加，进而转运 BDNF 被轴突释放并到达内侧前额皮质目标，然后导致突触增加。内侧前额叶皮层与其下游目标、基底外侧杏仁核和因此，目标追踪者需要提高使用情境的能力。来自海马输入并通过内侧前额叶皮层传递的信息，适当地修改皮质下对与情绪显着事件相关的线索的反应。与 NIH 和 NIDA 的使命高度一致，因为它将有助于阐明成瘾的神经生物学途径以及经常同时发生的疾病，这是一个重要的公共卫生优先事项。