Endocannabinoids and the modulation of expectation

内源性大麻素和期望的调节

• 批准号: 8495302
• 负责人: Joseph F Cheer
• 金额: $ 11.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495302
• 关键词: Abstinence; Address; Afferent Pathways; Agonist; Behavioral; Benzodiazepines; Brain; Brain region; CNR1 gene; Calcium Channel Blockers; Cannabinoids; Cell Nucleus; Cholecystokinin; Clinical; Cognitive; Crisis Intervention; Cues; Cycloserine; Data; Dependence; Development; Dissection; Dopamine; Drug Addiction; Drug Metabolic Detoxication; Drug abuse; Endocannabinoids; Event; Exhibits; Expectancy; Experimental Designs; Extinction (Psychology); GTP-Binding Proteins; Genes; Genetic; Harm Reduction; Institutes; Interneurons; Knockout Mice; Lasers; Learning; Lighting; Link; Mediating; Messenger RNA; Midbrain structure; Motor; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurons; Nucleus Accumbens; Obsessive-Compulsive Disorder; Outcome; Output; Pathology; Patients; Pattern; Population; Prefrontal Cortex; Preparation; Process; Proteins; Psychopathology; Pyramidal Cells; Receptor Signaling; Recruitment Activity; Relapse; Reporting; Reversal Learning; Rewards; Role; Signal Transduction; Site; Stimulus; Syndrome; System; Testing; Therapeutic; Time; Tissues; Training; Transfection; Ventral Tegmental Area; anandamide; base; classical conditioning; conditioned fear; drug craving; expectation; experience; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; insight; learning extinction; neural circuit; neurobiological mechanism; neuromechanism; neuronal cell body; novel; optogenetics; post-traumatic stress; promoter; receptor; receptor coupling; receptor expression; recombinase; relating to nervous system; response; therapeutic target; tool; vector; voltage

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.

描述(由申请人提供)：这项提案将调查与CB1受体阻滞剂1对关键联想学习回路中的消失过程的良好记录的影响相关的神经机制。眼眶前额叶皮质(OFC)在 比较预期和实际回报结果的计算2。我们先前的研究表明，伏隔核(NAC)(边缘-运动接口)的放电和亚秒多巴胺释放的一致变化与腹侧被盖区(VTA)的脑刺激奖励(BSR)期间的奖赏可获得性信号有关。线索引起的DA释放的变化被认为是编码奖励预测错误的3，在灭绝条件下消失，并根据实验者提供的先前与BSR4相关的线索迅速重新建立。这是通过给予CB1受体拮抗剂来模拟的。在这里，我们将研究OFC中的内源性大麻素信号如何调节行为反应和巴甫洛夫过度期望期间的实时多巴胺信号。初步数据显示，OFC神经元在超乎预期的情况下表现出短暂的持续活动2。这种活动模式类似于在其他皮质区域5-11产生内源性大麻素介导的可塑性所需的模式。鉴于大麻类物质能够通过特定的OFC相关性损害逆转学习12，我们将研究OFC中的内源性大麻素信号在过度预期导致的灭绝中的作用以及伴随着NAC中亚秒多巴胺释放的变化。这些研究将解决OFC中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。干扰或促进位于多巴胺细胞体上游的OFC中的内源性大麻素张力，可能会深刻影响神经回路对结果预测环境刺激的反应方式。这一假说从未被直接验证过，因为要做到这一点，需要有选择地在与认知过程相关的解剖学上精确的大脑轨迹上调节内源性大麻素的释放。在这里，我们将分离内源性大麻素招募的传入通路，以在过度预期期间产生模式的OFC活动。CB1受体对OFC锥体神经元抑制性传入的特异性遗传控制和对该回路的光遗传学询问将允许明确测试皮质内大麻素功能及其对在消退训练中预测错误的多巴胺编码的影响。通过研究过度期望学习过程中多巴胺能和内源性大麻素信号之间的相互作用，本提案将产生与基于灭绝的治疗策略相关的新见解。