Activity Dependence of Endocannabinoid Signaling

内源性大麻素信号传导的活性依赖性

• 批准号: 7674980
• 负责人: MICHAEL MYOGA
• 金额: $ 3.21万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674980
• 关键词: Action Potentials; Acute; Address; Alcohols; Area; Biological Assay; Brain; Calcium; Calcium Signaling; Cells; Cocaine; Cognition; Dependence; Desire for food; Development; Drug Delivery Systems; Drug abuse; Electrophysiology (science); Endocannabinoids; Frequencies; GTP-Binding Proteins; Image; Lead; Learning; Long-Term Depression; Marijuana; Measures; Mediating; Memory; Motor; Nicotine; Obesity; Pain; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Photons; Physiological; Regulation; Rewards; Role; Signal Transduction; Signaling Molecule; Slice; Synapses; Synaptic plasticity; System; Testing; Time; Training; Withholding Treatment; addiction; autocrine; cannabinoid receptor; insight; novel; phospholipase C beta; postsynaptic; presynaptic; response; smoking cessation; stellate cell; therapeutic target

DESCRIPTION (provided by applicant): Endocannabinoids (eCBs) are important retrograde signaling molecules that regulate synaptic strength in many brain areas. They are released by postsynaptic cells and activate presynaptic G protein-coupled type- 1 cannabinoid receptors (CBIRs). CB1R signaling can induce both short-term and long-term depression (STD and LTD). CBIRs are the primary target of psychoactive constituents found in marijuana and have also been implicated in brain reward mechanisms. Previous studies have elucidated two cellular mechanisms that control eCB release: elevation of postsynaptic calcium and activation of postsynaptic phospholipase C-beta (PLCP). We will investigate how calcium and PLC(3 interact to control the activity dependence of eCB signaling at synapses onto cerebellar stellate cells (SCs) in acute brain slices. Interactions between calcium and PLCP are difficult to study without the ability to simultaneously measure postsynaptic calcium and synaptic strength. We will dissect contributions of postsynaptic calcium and PLCP to eCB signaling using electrophysiology, 2-photon calcium imaging and pharmacology. This will allow us to address two important issues regarding the activity dependence of eCB signaling. First, we will examine conditions that permit physiologically relevant patterns of spiking to evoke eCB signaling that induces STD or LTD. Second we will examine eCB signaling in response to brief, high frequency and prolonged, low frequency patterns of synaptic activation. Here, we will determine the contributions of postsynaptic calcium and PLCP to eCB signaling and assay for STD and LTD. Finally, we will investigate the role of eCB signaling in associating presynaptic and postsynaptic patterns of activity. Results from these studies will provide insight into the learning rules for STD and LTD. Understanding eCB signaling in SCs has specific importance for cerebellar function and also general importance for eCB signaling elsewhere in the brain. The endocannabinoid system is an intensely studied therapeutic target, because it is involved in brain areas that control learning, memory, motor coordination, appetite, cognition, pain and addiction. Recently, the first drug targeting brain cannabinoid receptors was introduced as an anti-obesity and smoking cessation treatment. Thus, understanding mechanisms that underlie the richness of endocannabinoid signaling provides promise for the development of novel drugs and therapies.

描述(申请人提供)：内源性大麻素(ECB)是重要的逆行信号分子，调节许多大脑区域的突触强度。它们由突触后细胞释放，激活突触前G蛋白偶联的1型大麻受体(CBIR)。CB1R信号可以诱导短期和长期的抑郁(STD和LTD)。CBIR是在大麻中发现的精神活性成分的主要靶点，也与大脑奖励机制有关。以往的研究阐明了控制ECB释放的两种细胞机制：突触后钙升高和突触后磷脂酶C-β(Plcp)的激活。我们将研究钙和PLC(3)如何相互作用来控制ECB信号在突触对小脑星状细胞(SCs)的活性依赖性。如果没有同时测量突触后钙和突触强度的能力，就很难研究钙和PLCP之间的相互作用。我们将使用电生理学、双光子钙成像和药理学来剖析突触后钙和PLCP在ECB信号中的作用。这将使我们能够解决有关欧洲央行信号活动依赖的两个重要问题。首先，我们将研究允许生理上相关的尖峰模式来激发ECB信号从而诱导STD或LTD的条件。其次，我们将研究ECB信号对短暂、高频和长时间、低频率突触激活模式的反应。在这里，我们将确定突触后钙和PLCP在ECB信号和STD和LTD检测中的作用。最后，我们将研究ECB信号在联系突触前和突触后活动模式中的作用。这些研究的结果将为STD和LTD的学习规则提供洞察力。了解干细胞中的ECB信号对小脑功能具有特殊的重要性，对大脑其他部位的ECB信号也具有普遍重要性。内源性大麻素系统是一个被广泛研究的治疗靶点，因为它涉及大脑中控制学习、记忆、运动协调、食欲、认知、疼痛和成瘾的区域。最近，第一个靶向大脑大麻素受体的药物被引入作为抗肥胖和戒烟治疗。因此，了解丰富的内源性大麻素信号的机制为开发新的药物和疗法提供了希望。