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

项目摘要 虽然许多人尝试滥用药物，但只有一小部分人过渡到成瘾。研究个体差异 成瘾脆弱性是理解成瘾的神经生物学基础的关键一步。 吸毒的动机及其对大脑和行为的影响。DSMV的11个标准中有9个 诊断患有物质使用障碍的个体与药物或行为的强烈动机有关 成瘾性，特征是尽管有负面后果，但仍坚持寻求和服用药物。双 这种心理特征的性质激发了这项研究计划，该计划考虑了动机和 灵活性之前，药物的经验，以了解成瘾的脆弱性。表型行为 差异，称为迹象跟踪和目标跟踪，差异预测药物寻求的脆弱性。签名- 和目标跟踪特征在啮齿动物和人类中观察到，并且是一种有希望的特征区别， 描述了不同物种的成瘾脆弱性。迹象追踪者显示出对食物的强烈动机， 与目标追踪者相比，药物相关的离散线索。我们实验室最近的研究表明- 跟踪大鼠是不灵活的，继续对先前奖励的线索作出反应，即使当价值的价值。 奖励被降低了。总而言之，“追踪特质”的区别是一个值得探索的理想模型 个体差异的动机和灵活性之前的药物经验。但大脑是什么 这些特质差异背后的机制基底外侧杏仁核是一个关键的大脑部位， 编码的线索价值是关键支持双方的食欲动机和灵活性，通过其相互作用 下游靶点是脑桥核和岛叶皮层我们认为，个体差异 信号追踪者和目标追踪者的食欲动机和行为灵活性由不同的基底外侧核介导。 杏仁核投射到脑桥核和岛叶皮质。在这里，我们使用协调的神经生物学 方法来测试我们的假设的具体预测。首先，我们检查是否神经元活动在不同的 基底外侧杏仁核通路支持信号和目标追踪者的食欲动机。接下来，我们确定 无论这些电路是差分接合的还是对于驱动符号的柔性行为的变化至关重要的， 和目标追踪者的区别。然后，我们确定破坏基底外侧的影响， 杏仁核对下游丘脑核和岛叶皮层在食欲动机过程中的编码作用 和结果值的修改。最后，我们确定是否基底外侧杏仁核通路激活， 在最初的学习过程中，个体偏向于食欲动机或灵活的行为策略。我们 利用新的工具是第一个研究特定的基底外侧杏仁核通路的作用， 驱动着标志追踪者和目标追踪者的不同行为。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的预防和诊断战略。

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.