Endogenous Cannabinoid Control of Reward Substrates

奖励底物的内源性大麻素控制

• 批准号: 10612049
• 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/10612049
• 关键词: 2-arachidonylglycerol; Adult; Animals; Behavior Control; Behavioral; Brain; CCL4 gene; 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; Ethology; Funding; GTP-Binding Proteins; Genetic; Globus Pallidus; Harm Reduction; In Vitro; Infrastructure; Knowledge; Learning; Link; Maps; Mediating; Membrane; Messenger RNA; Methodology; Midbrain structure; Motivation; Mus; Negative Reinforcements; Neuromodulator; Nucleus Accumbens; Organism; Outcome; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Population; Populations at Risk; Positive Reinforcements; Probability; Process; Production; Punishment; Relapse; Rewards; Role; Signal Transduction; Site; Stimulus; Technology; Testing; Therapeutic; Time; Training; Transgenic Mice; Transgenic Model; Ventral Tegmental Area; Work; addiction; 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; neural; neurobiological mechanism; optogenetics; pharmacologic; postsynaptic; receptor; receptor expression; recruit; 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.

项目概要 大脑的主要功能之一是计算有机体做出的最适应性行动 在给定的环境条件下。这个过程需要了解其中的哪些功能 环境预测行为学相关性，并根据可能的情况决定采取哪些行动 这些行动的结果。因此，奖励预测的神经基质必须与那些控制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组成部分。多巴胺能 中脑神经元会因当前环境未预测到的奖励而兴奋。然而，当 刺激可靠地预测奖励，它们减少锁定奖励的活动时间并转向环境 预测者本身。因此，多巴胺被认为是一种传播刺激相关的教学信号。 奖励预测。之前资助周期的数据表明，腹侧的内源性大麻素 在奖励寻求过程中，被盖塑造了线索诱导伏隔核中多巴胺释放的激增。 我们假设，但从未明确证明，这是由于释放 来自多巴胺神经元本身的内源性大麻素 2AG，从而降低了它们的抑制水平。这 去抑制机制是高度保守的，因为我们发现它发生在追求欲望奖励的过程中 也是在逃避惩罚的过程中。然而，腹侧被盖的精确兴奋输入 负责从多巴胺神经元按需释放 2AG 的机制尚不清楚。在此，我们建议 进一步阐明内源性大麻素信号在奖励相关线索编码中的作用的实验 它在动机中的作用。首先，我们将使用基因解剖方法评估 2AG 是否确实是 多巴胺神经元释放的活动是否符合奖励预测理论以及是否可以 因果影响行为（目标 1）。接下来，我们将确定哪些 CB1 受体表达传入神经 VTA 中的多巴胺神经元负责提示驱动奖励期间 2AG 的去抑制作用 寻求。我们将通过研究兴奋性传入来为这些问题提供进一步的机制见解。 在追求奖励过程中引起 2AG 依赖性多巴胺神经元去抑制（目标 2）。这样，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 使用方法论整合的方法，作为 2AG 产生和 CB1 受体的特定遗传控制 表达将允许对当前内源性大麻素调节动机行为的假设进行明确的测试。 本提案利用尚未应用于这些问题的工具来产生关于这些问题的新见解 治疗动机障碍的治疗策略，例如适应不良的药物寻求。