Endogenous Cannabinoid Control of Reward Substrates

奖励底物的内源性大麻素控制

• 批准号: 10436157
• 负责人: Joseph F Cheer
• 金额: $ 38.88万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10436157
• 关键词: 2-arachidonylglycerol; Adult; Animals; Behavioral; Brain; CNR1 gene; Cell Nucleus; Cell membrane; Cells; Clinical; Crisis Intervention; Cues; Data; Disease; Disease remission; Disinhibition; Dissection; Dopamine; Educational process of instructing; Endocannabinoids; Environment; Enzymes; Funding; GTP-Binding Proteins; Genetic; Globus Pallidus; Harm Reduction; In Vitro; Infrastructure; Knowledge; Learning; Link; Mediating; Membrane; Messenger RNA; Methodology; Midbrain structure; Motivation; Mus; Negative Reinforcements; Neuromodulator; Nucleus Accumbens; Organism; Outcome; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Population; Populations at Risk; Positive Reinforcements; Probability; Process; Production; Punishment; Relapse; Rewards; Role; Signal Transduction; Site; Stimulus; Testing; Therapeutic; Time; Training; Transgenic Mice; Transgenic Model; Ventral Tegmental Area; Work; addiction; base; behavior influence; dopaminergic neuron; drug craving; drug withdrawal; endocannabinoid signaling; endogenous cannabinoid system; expectation; experience; experimental study; insight; lipoprotein lipase; motivated behavior; motivational processes; mouse model; neurobiological mechanism; optogenetics; postsynaptic; receptor; receptor expression; recruit; relating to nervous system; superior colliculus Corpora quadrigemina; theories; tool; treatment strategy

PROJECT SUMMARY One of the primary functions of the brain is to calculate the most adaptive action for the organism to make under a given set of environmental conditions. This process requires learning which features in the environment predict ethological relevance and subsequently deciding which actions to take, given the probable outcome of those actions. Hence, neural substrates for reward prediction must interact with those controlling behavioral output. The neuromodulator dopamine is a critical component of this interaction. Dopaminergic neurons in the midbrain are excited by rewards not predicted by the current environment. However, when stimuli reliably predict reward, they decrease activity time locked to the reward and shift to the environmental predictors themselves. Therefore, dopamine is thought of as a teaching signal that broadcasts stimuli-related reward predictions. Data from the previous funding cycles showed that endocannabinoids in the ventral tegmentum sculpt cue-induced surges in dopamine release in the nucleus accumbens during reward seeking. We hypothesized, but never unambiguously demonstrated, that this arises from release of the endocannabinoid 2AG from dopamine neurons themselves, which lessens their level of inhibition. This disinhibition mechanism is highly conserved as we found that it occurs during the pursuit of apetitive rewards but also during the avoidance of punishment. However, the precise excitatory input to the ventral tegmentum responsible for the on-demand release of 2AG from dopamine neurons is not known. Here, we propose experiments to further elucidate the role of endocannabinoid signaling in encoding of reward-related cues and its role in motivation. First, we will assess, using genetic dissection approaches, whether 2AG is indeed released from dopamine neurons for their activity to conform to reward prediction theories and whether it can causally influence behavior (aim 1). Next, we will determine which CB1 receptor-expressing afferents to dopamine neurons in the VTA are responsible for the disinhibitory actions of 2AG during cue-driven reward seeking. We will provide further mechanistic insight to these questions by studying the excitatory afferents that give rise to 2AG-dependent dopamine neuron disinhibition during the pursuit of rewards (aim 2). Thus, we will isolate the different components necessary for endocannabinoid signaling to modulate motivational processes using a methodologically-integrated approach, as specific genetic control of 2AG production and CB1 receptor expression will allow explicit tests of current hypotheses of endocannabinoid modulation of motivated behavior. The present proposal makes use of tools not yet applied to these questions to generate new insights on therapeutic strategies for the treatment of motivational disorders such as maladaptive drug seeking.

项目摘要 大脑的主要功能之一是计算生物体做出的最适应性的动作 在特定的环境条件下。这个过程需要了解 环境预测行为学的相关性，并随后决定采取哪些行动，鉴于可能的 这些行动的结果。因此，奖励预测的神经基质必须与控制奖励的神经基质相互作用。 行为输出神经调节剂多巴胺是这种相互作用的关键成分。多巴胺能 中脑中的神经元被当前环境所没有预测到的奖励所兴奋。然而当 刺激可靠地预测奖励，他们减少锁定奖励的活动时间，并转移到环境 预测者自己因此，多巴胺被认为是一种教学信号， 奖励预测前几个资助周期的数据显示，腹侧的内源性大麻素 在寻求奖励的过程中，被盖雕刻线索诱导的多巴胺释放激增。 我们假设，但从来没有明确证明，这是由于释放的 内源性大麻素2AG从多巴胺神经元本身，这降低了他们的抑制水平。这 去抑制机制是高度保守的，因为我们发现它发生在追求竞争性奖励的过程中 而且是在逃避惩罚的时候然而，腹侧被盖的精确兴奋性输入 负责从多巴胺神经元按需释放2AG的基因尚不清楚。在这里，我们建议 进一步阐明内源性大麻素信号在编码奖励相关线索中的作用的实验， 它在动机中的作用。首先，我们将使用遗传解剖方法评估2AG是否确实是 从多巴胺神经元释放的活动，以符合奖励预测理论，以及它是否可以 影响行为（目标1）。接下来，我们将确定哪种表达CB1受体的传入神经 腹侧被盖区的多巴胺神经元负责线索驱动奖赏过程中2AG的去抑制作用 寻找我们将通过研究兴奋性传入， 在追求奖赏的过程中引起2AG依赖性多巴胺神经元去抑制（目的2）。因此，我们将 分离内源性大麻素信号传导调节动机过程所需的不同成分 使用方法学整合的方法，作为2AG产生和CB 1受体的特异性遗传控制， 表达将允许明确测试动机行为的内源性大麻素调节的当前假设。 本提案利用尚未适用于这些问题的工具， 治疗动机障碍的治疗策略，如适应不良的药物寻求。