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: 8344688
• 负责人: David M Lovinger
• 金额: $ 75.82万
• 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/8344688
• 关键词: Agonist; Animals; Antipsychotic Agents; Arbitration; Attention deficit hyperactivity disorder; Autoreceptors; Basal Ganglia; Behavior; Behavior Control; Behavioral; Brain; Brain region; Breathing; CNR1 gene; Cocaine; Corpus striatum structure; Deglutition; Disease; Dopamine; Dopamine D2 Receptor; Dorsal; Drug Delivery Systems; Drug usage; Elements; Endocannabinoids; Environment; Enzymes; Event; Exhibits; Experimental Designs; Feedback; Food; Fostering; Future; Genetic; Glutamates; Goals; Grooming; Habits; Haloperidol; Health; Hyperactive behavior; Implant; Injection of therapeutic agent; Interneurons; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Life; Link; Locomotion; Mediating; Methylphenidate; Midbrain structure; Modeling; Molecular; Movement; Mus; Neocortex; Neurobiology; Neurons; Neurotransmitters; Operant Conditioning; Outcome; Pattern; Performance; Pharmaceutical Preparations; Physiological; Play; Process; Psychological reinforcement; Psychology; Reagent; Receptor Gene; Research; Response to stimulus physiology; Rewards; Ritalin; Role; Schedule; Sorting - Cell Movement; Speed; Stimulus; Study Section; Substance abuse problem; Substantia nigra structure; Symptoms; Synapses; Tamoxifen; Task Performances; Training; Tyrosine 3-Monooxygenase; Work; addiction; dopaminergic neuron; drug of abuse; enzyme activity; experience; feeding; habit learning; improved; knockout animal; neural circuit; novel; pars compacta; postsynaptic; preference; presynaptic; prevent; receptor; recombinase; research study; response; skills; transmission process

Dopamine autoreceptor roles in striatal function and behavior Dopaminergic transmission in striatum is involved in action selection, movement initiation, reward, reinforcement and responses to drugs of abuse. Dopamine (DA) produces its physiological actions through the activation of 5 receptor subtypes. Within the striatum, two subtypes, D1 and D2, predominate. The D2 receptor has a variety of physiological roles within the striatum. This receptor is also the major target for antipsychotic drugs, and levels of D2 expression have been related to liability for substance abuse disorders. However, D2 receptors are present on a variety of neuronal subtypes within the striatum. Receptors are present postsynaptically on striatal medium spiny neurons and interneurons. Presynaptic D2 receptors are present on glutamatergic afferents coming from the neocortex and dopaminergic afferents from the Substantia Nigra pars compacta. These latter receptors, known as autoreceptors, are intriguing in that they provide feedback inhibitory control of DA release in striatum, often opposing the effects of the postsynaptic D2 receptors. Sorting out the actions of the D2 receptors on different striatal cellular elements has been difficult in past studies due to the lack of suitably specific pharmacological reagents that can separately target the different receptors. We have worked with Dr. Marcelo Rubinstein, who developed mice in which the D2 receptor was selectively eliminated from midbrain dopaminergic neurons using a Cre recombinase action on a loxP-flanked D2 receptor construct (termed autoDrd2KO mice). We performed voltammetric studies to examine DA release in the dorsal striatum of these mice. Increased DA release was observed in striatum in the autoDrd2KO mice, that appeared to be linked to increased activity of the enzyme tyrosine hydroxylase (the rate-limiting enzyme for DA synthesis). This finding supports the idea that D2 autoreceptors inhibit DA synthesis through actions on the enzyme. The normal inhibitory effect of D2 activation on DA release was also lost in the autoDrd2KO mice, providing additional support for the loss of autoreceptor feedback inhibition. When short trains of stimulation were given to activate DA release over a period of several seconds, there is normally an initial surge of DA release followed by a rapid decrease in neurotransmitter levels, reaching a sustained steady state level. Application of a D2 receptor antagonist allows for sustained high levels of DA release, and this effect was mimicked in the autoDrd2KO mouse striatum. Furthermore, D2 antagonist treatment had no effect on the sustained high DA levels produced by repeated afferent stimulation in the autoDrd2KO mouse striatum. These findings indicate that an important autoreceptor role is to curtail DA release during short phasic bursts of afferent activity, preventing excessive DA release. It appears that the D2 receptor is the predominant, if not exclusive, DA autoreceptor, at least in mouse striatum. The autoDrd2KO mice exhibited hyper-locomotion in a novel environment, with sustained higher levels of activity even when mice were familiarized with the environment. The mice were hyper-sensitive to treatment with D2 agonist, most likely due to enhanced effect of postsynaptic receptor actions. The autoDrd2KO mice were also more sensitive to movement inhibition produced by the D2 antagonist haloperidol, suggesting a role for autoreceptors in limiting effects of antipsychotic D2-targeted drugs. The autoDrd2KO mice were hypersensitive to locomotor activation by cocaine, and showed increased place preference for cocaine. In addition, these mice showed greater persistence in operant tasks motivated by food reward. These findings indicate that D2 autoreceptors play key roles in limiting hyperactivity and response to antipsychotic drugs. In addition, the evidence from this study indicates that these autoreceptors regulate the effects of natural rewards and drugs of abuse, perhaps limiting abuse liability. In ongoing studies we are examining the effects of drugs used to treat attention deficit hyperactivity disorder (ADHD) in the hyperdopaminergic/hyperactive autoDrd2KO mice. These mice may serve as a useful model for aspects of ADHD, allowing us to determine how drugs such as methylphenidate (Ritalin) alter striatal function to alleviate ADHD symptoms. In future studies we can use the loxP-flanked D2 mice developed by Dr. Rubinstein to examine physiological and behavioral roles of D2 receptors on other cellular elements within the striatum. Dissecting the roles in instrumental learning of CB1 receptors on different striatal afferents Instrumental learning allows animals to acquire new behaviors to adapt to environmental demands. Research in behavioral psychology has identified two separable processes that take place during instrumental learning. One process, termed action-outcome (A-O, also known as goal-directed) learning, involves behavior that is sensitive to the proximal outcome of the action. The learning process known as stimulus-response (S-R, or habitual) learning is expressed as behavior that is driven by the context, independent of the proximal outcome. Previous studies from our laboratory group indicated that CB1 endocannabinoid receptors play a crucial role in S-R learning. We have now examined roles of CB1 receptors present on different cellular elements within striatum in A-O and S-R instrumental learning. To do this we have employed mice expressing loxP-flanked CB1 receptor genes, and interbred them with mice expressing the cre recombinase in different cortical and striatal neuronal subtypes. Mice are then trained on an instrumental lever-pressing task in two separate environments, using reward schedules that foster A-O learning (random ratio training) or S-R learning (random interval training). Using a tamoxifen-inducible Cre mouse, we have been able to knock out CB1Rs in the neocortex. Knockout animals learned the lever pressing task with performance equivalent to wildtype mice. However, regardless of training schedule, the cortical CB1R knockout mice showed evidence of A-O and not S-R learning. This finding suggests that receptors expressed on cortical projection neurons play a crucial role in S-R habitual learning. The orbitofrontal cortex is one subcortical region that likely plays a role in arbitrating between A-O and S-R control of behavior. Using local injections of tamoxifen, we can explore the role of OFC CB1 receptors in these forms of learning. Current experiments are aimed at determining the participation of CB1 receptors at synapses in striatum, including corticostriatal glutamatergic and intrastriatal GABAergic synapses, in instrumental learning. We are also recording the activity of single neurons in the OFC as well as dorsomedial and dorsolateral striatum in mice as they learn and perform the instrumental bar-pressing task under the random ratio and random interval schedules. The use of chronically implanted multielectrode arrays allows us to examine multiple neurons in the same brain region simultaneously. The unique experimental design in which animals perform in separate contexts with separate schedules on the same day, allows us to examine the same neuron in the two different training situations. Findings in wildtype mice indicate that neurons in these brain regions show different patterns of lever-press related firing in the different training contexts, as well as differential responses when the outcome retains its value or is devalued by pre-feeding. Experiments are ongoing to determine how loss of CB1 receptors alters neuronal activity in relation to task performance.

多巴胺自身受体在纹状体功能和行为中的作用 纹状体中的多巴胺能传播参与了行动选择，运动启动，奖励，增强和对滥用药物的反应。多巴胺（DA）通过激活5种受体亚型产生其生理作用。 在纹状体中，两个亚型D1和D2占主导地位。 D2受体在纹状体中具有多种生理作用。 该受体也是抗精神病药的主要靶标，D2表达水平与药物滥用疾病的责任有关。 但是，纹状体内的多种神经元亚型存在D2受体。受体在纹状体培养基神经元和中间神经元上出现后突触。 来自新皮层的谷氨酸能传入和多巴胺能传入的传入中存在突触前的D2受体，来自黑质Nigra pars compacta。 这些后一种被称为自感受器的受体令人着迷，因为它们提供了对纹状体中DA释放的反馈抑制控制，通常会反对突触后D2受体的作用。 在过去的研究中，由于缺乏适当特定的药理学试剂，可以分别靶向不同受体，因此在过去的研究中很难整理D2受体对不同纹状体细胞元素的作用。 我们已经与Marcelo Rubinstein博士合作，后者开发了小鼠，其中使用CRE重组酶在LOXP-FALKANK的D2受体构建体（称为AutodRD2KO小鼠）上使用CRE重组酶作用选择性地从中脑多巴胺能神经元中消除了D2受体。 我们进行了伏安学研究，以检查这些小鼠背纹状体中的DA释放。 在AutoDRD2KO小鼠的纹状体中观察到DA释放的增加，这似乎与酪氨酸酪氨酸羟化酶的活性增加有关（DA合成的速率限制酶）。 这一发现支持了D2自动受体通过对酶的作用抑制DA综合的想法。 D2激活对DA释放的正常抑制作用在AUTODRD2KO小鼠中也丢失，为自动受体反馈抑制的丧失提供了更多支持。 当给出短刺刺激以在几秒钟内激活DA释放时，通常会出现DA释放的初始激增，然后神经递质水平迅速降低，达到持续的稳态水平。 D2受体拮抗剂的应用允许持续的高水平DA释放，并且在AutoDRD2KO小鼠纹状体中模仿了这种效果。 此外，D2拮抗剂治疗对自动d2ko小鼠纹状体的反复传入刺激产生的持续高DA水平没有影响。 这些发现表明，重要的自身受体作用是在短期的传入活动中减少DA释放，从而防止过度释放DA。 至少在小鼠纹状体中，D2受体似乎是主要的，即使不是专属的DA自感受器。 AutoDRD2KO小鼠在新型环境中表现出超恢复性，即使小鼠熟悉环境，其活性也持续更高。 小鼠对用D2激动剂的治疗非常敏感，这很可能是由于突触后受体作用的影响增强所致。 AutoDRD2KO小鼠对D2拮抗剂氟哌啶醇产生的运动抑制也更为敏感，这表明自身受体在限制抗精神病药D2靶向药物的效果中的作用。 自drd2ko小鼠对可卡因对运动的激活过敏，并显示出可卡因的位置偏好。 此外，这些小鼠在以食物奖励的启发的操作任务中表现出更大的持久性。 这些发现表明，D2自动受体在限制多动症和对抗精神病药的反应中起关键作用。 此外，这项研究的证据表明，这些自身受体调节自然奖励和滥用药物的影响，也许限制了滥用责任。 在正在进行的研究中，我们正在研究用于治疗高多巴胺能/多动态自动型自动d2KO小鼠中注意力缺陷多动障碍（ADHD）的药物的作用。 这些小鼠可以作为多动症方面的有用模型，从而使我们能够确定甲基苯甲酸酯（Ritalin）等药物如何改变纹状体功能以减轻ADHD症状。 在未来的研究中，我们可以使用Rubinstein博士开发的LOXP频闪的D2小鼠来检查D2受体在纹状体内其他细胞元素上的生理和行为作用。 剖析不同纹状体传入中CB1受体的仪器学习中的作用 乐器学习使动物可以获取新的行为以适应环境需求。 行为心理学的研究已经确定了在乐器学习过程中发生的两个可分离过程。 一个被称为动作结果的过程（A-O，也称为目标定向）学习，涉及对动作近端结果敏感的行为。 被称为刺激反应（S-R或习惯性）学习的学习过程表示为由上下文驱动的行为，与近端结果无关。 我们实验室组的先前研究表明，CB1内源性大麻素受体在S-R学习中起着至关重要的作用。 现在，我们研究了A-O和S-R器械学习中纹状体内不同细胞元素中存在的CB1受体的作用。 为此，我们采用了表达LOXP flankP的CB1受体基因的小鼠，并将它们与在不同皮质和纹状体神经元亚型中表达CRE重组酶的小鼠交流。 然后，使用奖励A-O学习（随机比率训练）或S-R学习（随机间隔训练），在两个单独的环境中对仪器杠杆压榨任务进行了培训。 使用他莫昔芬诱导的CRE小鼠，我们能够在新皮层中淘汰CB1R。 敲除动物以相当于野生型小鼠的性能学习了杠杆紧迫的任务。 但是，无论训练时间表如何，皮质CB1R敲除小鼠都显示出A-O而不是S-R学习的证据。 这一发现表明，在皮质投射神经元上表达的受体在S-R惯性学习中起着至关重要的作用。 眶额皮质是一个下皮质区域，可能在A-O和S-R的行为控制之间起作用。 使用他莫昔芬的局部注射，我们可以探索OFC CB1受体在这些学习形式中的作用。 当前的实验旨在确定CB1受体参与纹状体中的突触，包括皮质纹状体谷氨酸能和纹状体内GABA能突触，在仪器学习中。 我们还记录了OFC中单个神经元的活性以及小鼠的背外侧纹状体和背外侧纹状体的活性，因为它们在随机比例和随机间隔时间表下学习和执行了仪器棒压紧任务。 长期植入的多电极阵列的使用使我们能够同时检查同一大脑区域中的多个神经元。 在同一天，动物在单独的时间表中在单独的情况下进行的独特实验设计使我们能够在两种不同的训练情况下检查相同的神经元。 野生型小鼠中的发现表明，这些大脑区域中的神经元在不同的训练环境中显示出不同的杠杆式压力射击模式，以及当结果保留其价值或通过预喂养贬值时，差异反应。 正在进行实验以确定CB1受体损失如何改变与任务性能有关的神经元活动。