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: 10452696
• 负责人: Jonathan David Morrow
• 金额: $ 45.71万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452696
• 关键词: Accounting; Affect; Affective; Amygdaloid structure; Animal Model; Automobile Driving; Aversive Stimulus; Axonal Transport; Behavior; Behavioral; Brain-Derived Neurotrophic Factor; Child Care; Chromatin Structure; Clinical Research; Complex; Conditioned Reflex; Cues; Data; Desire for food; 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 Groups; Mission; Modification; Molecular; Motivation; National Institute of Drug Abuse; Negative Valence; Neurobiology; Neurons; Nucleus Accumbens; Outcome Measure; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Phenotype; Population; Positive Valence; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prevention strategy; Procedures; Process; Rattus; Regulation; Relapse; Research; Research Project Grants; Rewards; Societies; Stimulus; Structure; Synapses; Techniques; Testing; United States National Institutes of Health; Variant; Viral Vector; Work; addiction; classical conditioning; cocaine self-administration; comorbidity; conditioned fear; conditioning; diagnostic tool; 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; psychiatric comorbidity; public health priorities; rational design; response; substance use; synaptogenesis; 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.

项目摘要/摘要 这项研究项目的重点是确定共同的神经生物学底物，使易损性既 与成瘾和创伤后应激障碍(PTSD)等经常共生的疾病有关。巴甫洛夫式 条件反射程序将被用来区分倾向于将高水平的 对离散预测线索的激励意义，而在很大程度上忽略了上下文，从 更多地利用语境来适当地调整他们的情绪反应。跟踪手势的个人是 与目标追踪者相比，更容易出现上瘾和创伤后应激障碍的行为。这些疾病的神经生物学基础 将通过测试动态中手势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 已知的关键边缘环路内的连通性调节动机行为，即来自腹侧的通路 海马体到内侧前额叶皮质到基底外侧杏仁核和伏隔核。表观遗传变化 而生长因子的表达也将通过病毒载体进行操纵，以测试对 对欲望和厌恶的线索和背景的条件性动机反应，以及 对感兴趣的边缘通路内的连接性和突触效率的电生理测量。 这些实验将检验这样一种假设，即目标追踪者中组蛋白乙酰化水平相对于符号- 行为条件化后的跟踪者导致BDNF转录增加，进而被转运 并释放到内侧前额叶皮质靶点。脑源性神经营养因子随后导致突触增加 内侧前额叶皮质与其下游靶区、杏仁基底外侧核和 伏隔核。因此，假设目标跟踪器具有更大的使用上下文的能力 来自海马输入的信息，并通过内侧前额叶皮质传递到适当的 修改皮质下对与情绪显著事件相关的线索的反应。这个建议的R01项目是 与NIH和NIDA的使命很好地一致，因为它将有助于澄清成瘾的神经生物学途径 和频繁的共生疾病，这是一个重要的公共卫生优先事项。