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: 9978012
• 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/9978012
• 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.

项目概要 虽然许多人尝试滥用药物，但只有一小部分人转变为成瘾。研究个体差异 成瘾脆弱性是理解成瘾神经生物学基础的关键一步 药物的动机及其对大脑和行为的影响。 DSMV 标准中的 9 项 诊断患有药物滥用障碍的个体与药物或行为的动机增强有关 缺乏灵活性，其特点是不顾负面后果仍坚持寻求和吸食毒品。双重 这种心理特征的本质激发了这项研究计划，该计划考虑了动机和 吸毒前的灵活性，以了解成瘾的脆弱性。表型行为 称为“迹象跟踪”和“目标跟踪”的差异可以不同地预测对毒品寻求的脆弱性。符号- 在啮齿类动物和人类中观察到目标跟踪特征，并且是一种有希望的特征区分 描述跨物种的成瘾脆弱性。迹象追踪器显示出对食物和食物的更高的动机 与目标追踪器相比，与药物相关的离散线索。我们实验室最近的工作表明， 跟踪老鼠不灵活，会继续对先前奖励的线索做出反应，即使奖励的价值 奖励已降级。总而言之，“跟踪特征”的区别是一个值得探索的理想模型 药物体验前的动机和灵活性存在个体差异。但大脑是什么 这些特征差异背后的机制是什么？基底外侧杏仁核是大脑最初的关键部位 提示值的编码是通过其交互支持食欲动机和灵活性的关键 下游目标是伏隔核和岛叶皮质。我们建议个体差异 信号跟踪器和目标跟踪器的食欲动机和行为灵活性是由不同的基底外侧介导的 杏仁核投射到伏隔核和岛叶皮质。在这里我们使用协调神经生物学 测试我们假设的具体预测的方法。首先，我们检查神经元活动是否在不同的 基底外侧杏仁核通路支持信号跟踪器和目标跟踪器的食欲动机。接下来，我们确定 这些电路是否有差别地参与并且对于驱动信号的灵活行为的变化至关重要 当结果价值变得更糟时，还有目标追踪器。然后，我们确定破坏基底外侧的影响 食欲动机期间杏仁核对下游伏隔核和岛叶皮质编码的输入 和结果值的修改。最后，我们确定基底外侧杏仁核通路是否激活 在最初的学习过程中，个体会偏向于有食欲的动机或灵活的行为策略。我们 利用新颖的工具成为第一个研究特定基底外侧杏仁核通路在 驱动标志跟踪器和目标跟踪器的独特行为。所提出的方法可能会产生新的生物标志物 成瘾脆弱性并确定治疗成瘾的新预防和诊断策略。