Corticostriatal mechanisms of action learning and habit formation

动作学习和习惯形成的皮质纹状体机制

• 批准号: 10922445
• 负责人: David M Lovinger
• 金额: $ 230.75万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10922445
• 关键词: 2-arachidonylglycerol; Acute; Alcohol consumption; Alcohols; Basal Ganglia; Behavior; Binding; Brain; Brain region; Breathing; CNR1 gene; Cannabis; Corpus striatum structure; Deglutition; Disease; Electric Stimulation; Endocannabinoids; Enzymes; Event; Excision; Fluorescence; Future; G-Protein-Coupled Receptors; Ganglia; Genetic; Goals; Grooming; Habits; Health; Heavy Drinking; Injections; Knockout Mice; Lead; Learning; Learning Skill; Life; Lipids; Measures; Mediating; Midbrain structure; Molecular; Motor Cortex; Mus; Neurobiology; Neurons; Outcome; Pathway interactions; Pattern; Peripheral Nervous System; Pharmaceutical Preparations; Process; Production; Prosencephalon; Receptor Activation; Receptor Inhibition; Reflex action; Role; Signal Transduction; Sleep; Sleep Architecture; Sleep disturbances; Slice; Speed; Spinal Cord; Stereotyping; Stimulus; Study Section; Substance Use Disorder; Substantia nigra structure; Symptoms; Synapses; Synaptic Transmission; Taste Perception; Tetrahydrocannabinol; Viral; Water; alcohol behavior; alcohol effect; alcohol exposure; alcohol use disorder; cannabinoid drug; cannabinoid receptor; cellular targeting; drug misuse; endocannabinoid signaling; experience; experimental study; genetic approach; habit learning; improved; in vivo; interest; lipoprotein lipase; male; member; mutant; neural circuit; neurotransmission; neurotransmitter release; preference; prevent; receptor; sedative; sensor

Striatonigral direct pathway 2-arachidonoylglycerol contributes to ethanol effects on synaptic transmission and behavior Endocannabinoids are lipid metabolites that activate cannabinoid receptors, the same receptors that are the major targets for delta-9-tetrahydrocannabinol, the major psychoactive ingredient in cannabis drugs. Endocannabinoid activation of the CB1 cannabinoid receptor inhibits release of neurotransmitters at synapses throughout the brain, spinal cord and peripheral nervous system. Activation of this receptor has been implicated in the control of alcohol intake and other alcohol-related behaviors. However, the roles in these behaviors of endocannabinoid signaling in specific brain regions and at specific synapses are not fully understood. The striatum, a subcortical brain region involved in action learning and control, expresses high levels of endocannabinoids and CB1 receptors. The dorsolateral striatum (DLS), a part of the forebrain sensorimotor circuitry, has been implicated in excessive alcohol intake. Thus, we hypothesized that alcohol alters endocannabinoid signaling in DLS and effects on this and other striatal subregions contribute to alcohol intake. To this end, we began by measuring endocannabinoid signaling in brain slices containing DLS. To measure endocannabinoid signaling at cortical inputs to DLS neurons we expressed the genetically-encoded fluorescent G protein-coupled receptor activation-based endocannabinoid sensor (GRABeCB2.0) in mouse primary motor cortex (M1) by in vivo viral injection. The GRABeCB2.0 sensor was then trafficked to cortical terminals in DLS. We prepared brain slices and used photometric recording to examine the fluorescent signals activated by electrical stimulation in DLS. As in our previous studies, we found that short bursts of electrical stimuli produced an increase in fluorescence that persisted for 10s of seconds. This increase was not observed with a mutant GRAB construct that does not bind endocannabinoids. The fluorescence increase was also prevented by a drug that blocks endocannabinoid binding to GRABeCB2.0 and a drug that blocks diacylglycerol lipase alpha (DGLalpha) the enzyme that catalyzes production of the endocannabinoid 2-arachidonoyl glycerol (2-AG). These findings are consistent with previous studies in our group indicating that 2-AG is the main endocannabinoid released following this pattern of electrical stimulation. We next used a genetic approach to determine which neurons in DLS produce the 2-AG we are detecting. In a previous study, we found that genetic removal of DGLalpha from all striatal spiny projection neurons (SPNs) eliminates stimulus-driven 2-AG release measured with GRABeCB2.0. In the persent study we specifically removed DGLalpha from only those SPNs that project to the substantia nigra pars reticulata (the "direct" pathway SPNs). Somewhat surprisingly, we found that this removal strongly reduced 2-AG release as measured with GRABeCB2.0. This indicates that the direct pathway SPNs contribute more strongly than expected to stimulation-induced 2-AG release in striatum. We then examined the effects of acute alcohol application on 2-AG release in brain slices expressing GRABeCB2.0 in M1 cortical terminals. Alcohol inhibited the stimulus-induced 2-AG release while the drug was present in the slice, and this effect was reversed when alcohol was removed from the slice. We also found that this acute alcohol exposure inhibited the small amount of 2-AG release that remained after DGLalpha removal from direct pathway SPNs. Thus, alcohol appears to reduce 2-AG release from all SPN subtypes. We next examined the potential role of 2-AG production from direct pathway SPNs in alcohol-related behaviors, with the rationale that the majority of release of this endocannabinoid in striatum comes from these neurons. We once again used mice in which DGLalpha was genetically removed from the direct pathway SPNs. We observed that the duration of alcohol-induced loss of righting reflex was reduced in the mice lacking direct pathway SPN DGLalpha. This suggests that 2-AG release from this SPN subtype contributes to the sedative effect of alcohol. We also performed a two-bottle choice alcohol drinking paradigm in the direct pathway SPN DGLalpa knockout mice and observed decreased alcohol preference and increased water preference in male, but not female mice. Changes in preference for sweet and bitter tasting substances was not altered these mice. Thus, 2-AG release from direct pathway SPNs and endocannabinoid signaling in striatum appear to have specific roles in control of alcohol drinking. In future experiments it will be interesting to determine what cellular targets of striatal endocannabinoid signaling contribute to the effects of alcohol. It will also be important to determine if other manipulations of striatal endocannabinoid and CB1 signaling, e.g. inhibition of 2-AG degradation, alter alcohol-related behaviors.

纹状体直接途径2-芳基烯丙基甘油有助于乙醇对突触传播和行为的影响 内源性大麻素是激活大麻素受体的脂质代谢产物，这是Delta-9-9-四氢大麻酚的主要靶标，这是大麻药物中主要的精神活性成分。 CB1大麻素受体的内源性大麻素激活抑制整个大脑，脊髓和周围神经系统的突触中神经递质的释放。该受体的激活与控制酒精摄入量和其他与酒精相关的行为有关。但是，在特定大脑区域和特定突触中内源性大麻素信号传导的这些行为中的作用尚未完全了解。纹状体是参与动作学习和控制的皮层下大脑区域，表达了高水平的内源性大麻素和CB1受体。背外侧纹状体（DLS）是前脑感觉运动电路的一部分，已与过量的酒精摄入有关。因此，我们假设酒精会改变DLS中的内源性大麻素信号传导，并对该纹状体和其他纹状体子区域的影响有助于酒精摄入量。 为此，我们首先测量含有DLS的脑切片中的内源性大麻素信号传导。为了测量DLS神经元皮质输入处的内源性大麻素信号传导，我们表达了基于遗传编码的荧光G蛋白偶联受体激活基于基于小鼠原发性运动皮层（M1）的基于基于内源性大麻素的传感器（grabecb2.0）。然后将GrabeCB2.0传感器贩运到DLS的皮质终端。我们准备了大脑切片并使用光度记录来检查DLS中电刺激激活的荧光信号。与以前的研究一样，我们发现短暂的电刺激爆发产生了荧光的增加，持续了10秒钟。没有结合内源性大麻素的突变抓取构建体观察到这种增加。荧光增加也是通过阻断内源性大麻素与grabecb2.0结合的药物，并阻止二酰基甘油脂肪酶α（dglalpha）的药物，该酶催化催化内源于内源性抗素的2-芳基酰烯酰烯酰烯酰甘油烯醇（2- ag）。这些发现与我们组以前的研究一致，表明2-AG是按照这种电刺激模式释放的主要内源性大麻素。接下来，我们使用一种遗传方法来确定DLS中哪些神经元产生的2-AG我们正在检测到。在先前的一项研究中，我们发现从所有纹状体棘刺神经元（SPN）中遗传去除DGLALPHA可消除用GrabeCB2.0测量的刺激驱动的2AG释放。在Persent研究中，我们仅从那些投射到黑质Nigra pars enticulata（“直接”途径SPN）的SPN中删除了DGLALPHA。令人惊讶的是，我们发现这种去除量大大降低了用grabecb2.0测量的2-AG释放。这表明直接途径SPNS对刺激诱导的2AG释放的预期贡献要强得多。 然后，我们检查了急性酒精应用对M1皮质末端表达grabecb2.0的脑切片中2 AG释放的影响。酒精抑制刺激诱导的2AG释放，而该药物存在于切片中，并且当从切片中除去酒精时，这种效果被逆转。我们还发现，这种急性酒精暴露抑制了从直接途径SPN中去除DGLALPHA后仍保留的少量2 AG释放。因此，酒精似乎减少了所有SPN亚型的2AG释放。 接下来，我们研究了直接途径SPN在酒精相关行为中的2AG产生的潜在作用，其理由是，这种内源性大麻素在纹状体中的大部分释放都来自这些神经元。我们再次使用了从直接途径SPN中遗传去除DGLALPHA的小鼠。我们观察到缺乏直接途径SPN dglalpha的小鼠中酒精诱导的矫正反射损失的持续时间减少。这表明从该SPN亚型释放2-AG释放有助于酒精的镇静作用。我们还在直接途径SPN DGLALPA敲除小鼠中进行了两瓶选择酒精饮酒范式，并观察到雄性但雌性小鼠的酒精偏好降低和含水量增加。这些小鼠的偏爱变化没有改变。因此，纹状体中直接途径SPN和内源性大麻素信号传导的2 AG释放似乎在控制饮酒方面具有特定的作用。 在将来的实验中，确定纹状体内源性大麻素信号传导的细胞靶标有助于酒精的影响会很有趣。确定纹状体内源性大麻素和CB1信号的其他操作是否也很重要，例如抑制2-AG降解，改变与酒精相关的行为。

项目成果

New twist on orphan receptor GPR88 function.

孤儿受体 GPR88 功能的新变化。

• DOI: 10.1038/nn.3244
• 发表时间: 2012
• 期刊: Nature neuroscience
• 影响因子: 25
• 作者: Lovinger,DavidM

Gestational ethanol exposure impairs motor skills in female mice through dysregulated striatal dopamine and acetylcholine function.

• DOI: 10.1038/s41386-023-01594-4
• 发表时间: 2023-11
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Bariselli, Sebastiano;Mateo, Yolanda;Reuveni, Noa;Lovinger, David M.
• 通讯作者: Lovinger, David M.

Wake up and smell the dopamine: new mechanisms mediating dopamine activity fluctuations related to sleep and psychostimulant sensitivity.

• DOI: 10.1038/s41386-020-00903-5
• 发表时间: 2021-03
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Kesner AJ;Lovinger DM
• 通讯作者: Lovinger DM

Corticostriatal Circuit Models of Cognitive Impairments Induced by Fetal Exposure to Alcohol.

• DOI: 10.1016/j.biopsych.2021.05.014
• 发表时间: 2021-10-15
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: Bariselli S;Lovinger DM
• 通讯作者: Lovinger DM

LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.

• DOI: 10.1038/nn.3636
• 发表时间: 2014-03
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Parisiadou, Loukia;Yu, Jia;Sgobio, Carmelo;Xie, Chengsong;Liu, Guoxiang;Sun, Lixin;Gu, Xing-Long;Lin, Xian;Crowley, Nicole A.;Lovinger, David M.;Cai, Huaibin
• 通讯作者: Cai, Huaibin