Individual Differences in Epigenetic Regulation of Emotional Learning

情绪学习表观遗传调节的个体差异

• 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
• 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

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.

项目总结/摘要 这个研究项目的重点是确定共同的神经生物学基板，赋予脆弱性， 成瘾和经常共同发生的疾病，如创伤后应激障碍（PTSD）。巴甫洛夫 条件反射程序将用于区分倾向于归因于高水平的 动机意义离散预测线索，而在很大程度上忽略了上下文，从“目标跟踪”大鼠， 更多地利用情境来适当地调整他们的情绪反应。跟踪信号的人 比目标追踪者更容易出现成瘾和创伤后应激障碍样行为。这些的神经生物学基础 行为特征将通过测试符号追踪者和目标追踪者之间的动态差异来探索。 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 已知介导动机性行为的关键边缘回路内的连接，即腹侧神经通路， 海马到内侧前额叶皮质到基底外侧杏仁核和丘脑核。表观遗传变化 和生长因子的表达也将使用病毒载体进行操作，以测试对 对食欲和厌恶线索和背景的条件性动机反应，以及 感兴趣的边缘系统通路内的连接性和突触效率的电生理学测量。 这些实验将检验这样一个假设，即目标追踪者的组蛋白乙酰化水平降低， 行为条件反射后的追踪器导致BDNF转录增加，反过来又被转运 轴突和释放到内侧前额叶皮质的目标。然后BDNF引起突触神经元的增加， 内侧前额叶皮层与其下游靶点基底外侧杏仁核和 丘脑核因此，目标追踪者被假设为具有更强的能力来使用上下文 来自海马输入并通过内侧前额叶皮层传递的信息， 改变皮层下对与情绪突出事件相关的线索的反应。本次R 01项目拟 这与NIH和NIDA的使命非常一致，因为它将有助于澄清成瘾的神经生物学途径 和经常并发的疾病，这是一个重要的公共卫生优先事项。