Endocannabinoids and the modulation of expectation

内源性大麻素和期望的调节

基本信息

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
项目类别：
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

项目摘要

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）：该提案将研究与关键关联学习回路中CB1受体阻断1对灭绝过程的据可查的影响相关的神经机制。眶额皮质（OFC）与比较预期与实际奖励结果的计算2。我们先前的研究表明，在边缘运动界面（NAC）（NAC）中的点火和多巴胺释放的重合变化与信号奖励腹侧刺激奖励（BSR）（VTA）（VTA）期间的奖励可用性的线索有关。提示诱发的DA释放的变化被认为编码奖励预测错误3，在灭绝条件下消失，并迅速重新确定了效率的实验者 - 先前与BSR4相关的提示。给药CB1受体拮抗剂可以模仿这一点。在这里，我们将研究OFC中的内源性大麻素信号如何调节帕夫洛维亚期间的行为反应和实时多巴胺信号传导。初步数据表明，OFC神经元在过度期望中表现出短暂的活性爆发2。这种活性模式类似于在其他皮质区域中产生内源性大麻素介导的可塑性所需的模式5-11。鉴于大麻素与特定OFC相关性损害逆转学习的能力12，我们将研究内源性大麻素信号传导在OFC中的作用在OFC中，在NAC中过度预测和随附多巴胺释放的变化引起的灭绝中。这些研究将解决OFC中内源性大麻素信号传导与阶段多巴胺能信号传导调节学习之间的相互作用。在OFC中干扰或促进内源性大麻素张力，多巴胺细胞体的上游可能会深刻影响神经回路对学习预测的学习刺激的响应方式。该假设从未直接检验，因为这样做需要选择性调制内源性大麻素在与认知过程相关的解剖学精确的脑基因座上释放。在这里，我们将隔离内源性大麻素在过度预测期间产生模式的OFC活性的传入途径。 CB1受体对OFC锥体神经元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对灭绝训练期间预测错误的多巴胺编码的皮质内源性内源性大麻素功能的明确检验。通过调查多巴胺能和内源性大麻素信号在学习过程中的相互作用之间的相互作用，本提案将产生与基于灭绝的治疗策略相关的新见解。