Endocannabinoids and the modulation of expectation

描述（由申请人提供）：本提案将研究与CB 1受体阻滞剂1对关键联想学习回路中消退过程的良好记录效应相关的神经机制。眶额皮质（OFC）是关键参与 比较预期与实际奖励结果的计算2.我们之前的研究表明，一致的变化，在发射和亚秒多巴胺释放的核中脑（NAc），边缘运动接口，与线索，信号奖励可用性在脑刺激奖励（BSR）的腹侧被盖区（VTA）。DA释放中的线索诱发的变化被认为编码了奖励预测错误3，在灭绝条件下消失，并在实验者先前与BSR相关的线索之后迅速重新建立4。这通过施用CB 1受体拮抗剂来模拟。在这里，我们将研究如何内源性大麻素信号在OFC调制行为反应和实时多巴胺信号在巴甫洛夫过度期望。初步数据显示，眶额皮层神经元表现出短暂的活动爆发在overexpectation 2。这种活动模式类似于在其他皮质区域产生内源性大麻素介导的可塑性所需的活动模式5 -11。考虑到大麻素损害逆转学习与特定OFC相关性的能力12，我们将研究内源性大麻素信号在OFC中的作用，以及NAc中亚秒级多巴胺释放的伴随变化。这些研究将阐明OFC中的内源性大麻素信号和相性多巴胺能错误信号之间的相互作用如何调节学习。干扰或促进多巴胺细胞体上游的OFC中的内源性大麻素音调，可能会深刻影响神经回路对结果预测环境刺激的学习反应方式。这一假设从未被直接验证过，因为要做到这一点，需要选择性地调节与认知过程相关的解剖学上精确的大脑部位的内源性大麻素释放。在这里，我们将分离的传入通路招募内源性大麻素产生模式OFC活动在过度期待。CB 1受体对OFC锥体神经元的抑制性传入的特定遗传控制和对该电路的光遗传学询问将允许明确测试皮质内源性大麻素功能及其对灭绝训练期间预测错误的多巴胺编码的影响。通过研究多巴胺能和内源性大麻素信号之间的相互作用，在学习过程中的过度期望，目前的建议将产生新的见解相关的预防为基础的治疗策略。 公共卫生相关性：药物滥用治疗的一个主要问题是，在长期戒断期之后，重新产生对药物的渴望和寻求环境诱因，即通常所说的复吸。临床经验表明，对成瘾患者进行危机干预、脱毒、稳定和减少危害的有效方法很少。通过在广泛的成瘾物质中采用具有有希望的治疗价值的新的药理学工具，将更好地了解在治疗药物成瘾和依赖中引发复发的神经生物学机制。

DESCRIPTION (provided by applicant): This proposal will investigate the neural mechanisms associated with the well-documented effects of CB1 receptor blockade1 on extinction processes in a key associative learning circuit. The orbitofrontal cortex (OFC) is critically involved in the computations that compare expected versus actual reward outcomes2. Our prior studies showed that coincident changes in firing and subsecond dopamine release in the nucleus accumbens (NAc), a limbic-motor interface, are linked to cues that signal reward availability during brain stimulation reward (BSR) of the ventral tegmental area (VTA). Cue-evoked changes in DA release thought to encode a reward prediction error3, disipate under extinction conditions and are rapidly re-instituted folowing experimenter- delivered cues previously asociated with BSR4. This is mimicked by administration of a CB1 receptor antagonist. Here, we will investigate how endocannabinoid signaling in OFC modulates behavioral responding and real-time dopamine signaling during Pavlovian over-expectation. Preliminary data shows that OFC neurons exhibit short lasting bursts of activity during over-expectation2. This activity pattern is similar to that required to produce endocannabinoid-mediated plasticity in other cortical areas5-11. Given the ability of cannabinoids to impair reversal learning with specific OFC correlates12, we will investigate the role of endocannabinoid signaling in the OFC in extinction induced by over-expectation and accompanying changes in subsecond dopamine release in the NAc. These studies wil address how interactions between endocannabinoid signaling in OFC and phasic dopaminergic error signaling modulate learning. Interfering with or facilitating endocannabinoid tone in the OFC, upstream from dopamine cell bodies, may profoundly impact the way neural circuits respond to outcome-predicting environmental stimuli for learning. This hypothesis has never been directly tested because to do so requires selective modulation of endocannabinoids release at anatomically precise brain loci related to cognitive processes. Here, we wil isolate the afferent pathway recruited by endocannabinoids to produce patterned OFC activity during over-expectation. Specific genetic control of CB1 receptors on inhibitory afferents to OFC pyramidal neurons and optogenetic interrogation of this circuit will allow explicit tests of cortical endocannabinoid function and its impact on dopamine encoding of prediction errors during extinction training. By investigating interactions between dopaminergic and endocannabinoid signaling during learning in over-expectation, the present proposal will generate new insights relevant to extinction-based therapeutic strategies. PUBLIC HEALTH RELEVANCE: A major problem in the treatment of drug abuse is the renewal of drug craving and seeking upon environmental triggers, commonly known as relapse, after protracted abstinence periods. Clinical experience indicates that there are few effective approaches for use in crisis intervention, detoxification, stabilization and harm reduction in addicted patients. By employing new pharmacological tools with promising therapeutic value in a broad spectrum of addictive substances, a better understanding of the neurobiological mechanisms triggering relapse in the treatment of drug addiction and dependence will be gained.