Role of basolateral amygdala projections in mediating individual differences in motivation and flexibility

基底外侧杏仁核投射在调节动机和灵活性个体差异中的作用

• 批准号: 10220916
• 负责人: Donna Calu Gogerdchi
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220916
• 关键词: Affect; Amygdaloid structure; Automobile Driving; Behavior; Behavioral; Biological Markers; Brain; Chronic; Cues; Desire for food; Diagnosis; Diagnostic; Disease; Early Diagnosis; Electrophysiology (science); Exhibits; Family; Food; Goals; Human; Individual; Individual Differences; Knowledge; Laboratories; Lead; Learning; Link; Mediating; Modeling; Modification; Motivation; Nature; Neurobiology; Neurons; Nucleus Accumbens; Outcome; Pathway interactions; Pharmaceutical Preparations; Policies; Prevention; Quality of life; Rattus; Relapse; Research; Rewards; Rodent; Role; Shapes; Site; Societies; Substance Use Disorder; Testing; Variant; Work; addiction; base; behavioral phenotyping; brain behavior; conditioning; drug of abuse; experience; flexibility; improved; in vivo; individual variation; novel; programs; psychologic; recreational drug use; tool; trait; treatment strategy

PROJECT SUMMARY While many individuals try drugs of abuse, only a subset transition to addiction. Studying individual differences in addiction vulnerability is a critical step towards understanding the neurobiological underpinnings of motivation for drugs and their impact on the brain and behavior. Nine of eleven of the DSMV criteria for diagnosing individuals with substance use disorder relate to heightened motivation for drugs or behavioral inflexibility, characterized by persistence to seek and take drugs despite negative consequences. The dual nature of this psychological profile inspires this research program, which considers both motivation and flexibility prior to drug experience in order to understand addiction vulnerability. Phenotypic behavioral differences, termed sign-tracking and goal-tracking, differentially predict vulnerability to drug seeking. Sign- and goal-tracking traits are observed in rodents and humans, and are a promising trait distinction for characterizing addiction vulnerability across species. Sign-trackers show heightened motivation for food- and drug-associated discrete cues compared to goal-trackers. Recent work from our laboratory shows that sign- tracking rats are inflexible, continuing to respond to previously rewarded cues, even when the value of the reward has been degraded. Taken together, the “tracking trait” distinction is an ideal model to explore individual differences in both motivation and flexibility prior to drug experience. But what are the brain mechanisms underlying these trait differences? The basolateral amygdala is a critical brain site for initial encoding of cue value that is key for supporting both appetitive motivation and flexibility through its interactions with downstream targets, the nucleus accumbens and insular cortex. We propose that individual differences in appetitive motivation and behavioral flexibility of sign- and goal-trackers are mediated by distinct basolateral amygdala projections to the nucleus accumbens and insular cortex. Here we use coordinated neurobiological approaches to test specific predictions of our hypothesis. Frist, we examine whether neuronal activity in distinct basolateral amygdala pathways supports appetitive motivation in sign- and goal-trackers. Next, we determine whether these circuits are differentially engaged and critical for driving variations in flexible behavior of sign- and goal-trackers when outcome value gets worse. Then, we determine the impact of disrupting basolateral amygdala input on encoding in downstream nucleus accumbens and insular cortex during appetitive motivation and modification of outcome value. Finally, we determine whether the basolateral amygdala pathway activated during initial learning biases the individual towards an appetitive motivated or flexible behavioral strategy. We make use of novel tools to be the first to investigate the role of specific basolateral amygdala pathways in driving the distinct behavior of sign- and goal-trackers. The proposed approaches may yield new biomarkers of addiction vulnerability and identify new prevention and diagnostic strategies for treatment of addiction.

项目总结 虽然许多人尝试滥用药物，但只有一小部分人过渡到上瘾。研究个体差异 易感性是了解成瘾的神经生物学基础的关键一步 毒品的动机及其对大脑和行为的影响。DSMV的11项标准中有9项 诊断药物使用障碍的个体与药物或行为动机的增强有关 不灵活，特征是不顾负面后果坚持寻求和服药。双重奏 这种心理侧写的性质启发了这个研究项目，该项目同时考虑了动机和 在毒品体验之前的灵活性，以便了解成瘾的脆弱性。表型行为 差异被称为标志跟踪和目标跟踪，它们不同地预测药物寻找的易感性。签署- 在啮齿动物和人类身上观察到了目标跟踪特征，这是一种有希望的特征区别 表征不同物种之间的成瘾易感性。标志跟踪器显示出对食物的强烈动机--以及 与目标追踪器相比，与药物相关的离散线索。我们实验室最近的研究表明，有迹象表明- 跟踪老鼠是不灵活的，它继续对之前奖励的提示做出反应，即使 报酬已经被降低了。总而言之，“跟踪特征”的区别是一个可以探索的理想模型 吸毒前在动机和灵活性上的个体差异。但是大脑是什么呢？ 这些特质差异背后的机制是什么？杏仁基底外侧核是早期脑内的关键部位。 对提示值进行编码，这是通过交互支持食欲动机和灵活性的关键 对于下游的靶点，伏隔核和岛叶皮质。我们认为，个体差异在 手势跟踪者和目标跟踪者的食欲动机和行为灵活性受不同的基线侧向调节 杏仁核向伏隔核和岛叶皮质投射。在这里，我们使用协调的神经生物学 测试我们假设的具体预测的方法。首先，我们检查了神经元活动是否不同于 杏仁核基底外侧通路支持手势和目标追踪者的食欲动机。接下来，我们确定 这些电路是否以不同方式接合，并对驱动符号灵活行为的变化至关重要- 当结果价值变得更差时，还有目标追踪器。然后，我们确定了破坏基底侧向的影响 杏仁核输入对食欲刺激伏隔核下游核和岛叶皮质编码的影响 以及对结果值的修改。最后，我们确定基底外侧杏仁核通路是否激活。 在最初的学习中，个体偏向于一种有食欲、有动机或灵活的行为策略。我们 利用新的工具首次研究特定的杏仁基底外侧核通路在脑内的作用 推动着手势追踪者和目标追踪者的独特行为。建议的方法可能会产生新的生物标志物 为治疗成瘾确定新的预防和诊断战略。