Alpha 7 nicotinic receptor-mediated enhancement of reinforcement learning

Alpha 7 烟碱受体介导的强化学习增强

基本信息

批准号：
8700975
负责人：
Jared William Young
金额：
$ 23.25万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700975
关键词：
Adverse effects Amphetamines Animals Behavior Behavior Therapy Biological Models Bipolar Disorder Clinical Cognition Cognitive Cognitive deficits Corpus striatum structure Data Disease Dopamine Dopamine Agonists Dopamine D1 Receptor Dopamine D2 Receptor Dose Drops Effectiveness Exhibits Facilities and Administrative Costs Genetic Gilles de la Tourette syndrome Haloperidol Human In Vitro Independent Living Intervention Knock-out Knockout Mice Lead Learning Levodopa Ligands Link Measures Mediating Mental disorders Modality Mus Mutant Strains Mice National Institute of Mental Health Nicotine Nicotinic Receptors Parkinson Disease Pathway interactions Patients Pharmacological Treatment Pharmacotherapy Phenotype Population Positive Reinforcements Process Psychological reinforcement Punishment Receptor Activation Recording of previous events Rewards Role Schedule Schizophrenia Side Speed Stimulus Techniques Testing Therapeutic Time Uncertainty Viral Work acetylcholine receptor agonist base classical conditioning cost improved in vivo innovation methyllycaconitine null mutation productivity loss public health relevance receptor response severe mental illness treatment effect virus genetics

项目摘要

DESCRIPTION (provided by applicant): For those with severe mental illness, cognitive deficits are the core impediment to their independent living. Treatments to improve cognition are urgently needed, but no new pharmacotherapies have been approved in over a decade. Psychotherapeutic interventions remain helpful but exhibit only moderate effect sizes. Because these interventions predominantly aid learning through positive reinforcement strategies, augmenting such learning with pharmacotherapies should synergistically enhance the effectiveness of those interventions. Striatal dopamine D1 receptors contribute to positive reinforcement learning but directly targeting these receptors produce undesirable side-effects. Activating the a7 nicotinic acetylcholine receptor (nAChR) indirectly activates striatal dopamine D1 receptors, providing a link between the a7 nAChR and positive reinforcement learning. This project will identify dopaminergic and nAChR pro-learning treatments and determine whether their effects are mediated by striatal dopamine D1 receptors. Reward- and punishment- related learning will be measured using the probabilistic learning (PL) task. The PL task rewards and punishes responding to both target and non-target stimuli. Selecting the target stimulus is normally rewarded (80%) but occasionally punished (20%). For the non-target stimulus, the reward/punishment schedule is reversed. Thus importantly, the PL task measures the speed at which the animal acquires contingencies during uncertainty and modulates its behavior as a function of reward history. Selecting the same side after a reward (win-stay) is beneficial only after a target response, while shifting after a loss is beneficial only after a non-target response reflecting good reward- and punishment-associative learning respectively. The indirect dopamine agonist levodopa improves PL via enhancing reward-associative learning in both healthy humans and Parkinson's patients. Similarly, we demonstrated an amphetamine- (another indirect dopamine agonist) and nicotine- (a general nAChR agonist) induced improvement of PL in mice via enhancing reward-associative learning. Specific Aim 1 will identify pro-learning doses of amphetamine, nicotine, and the selective a7 nAChR agonist PNU 282987, utilizing amphetamine as a positive control. Specific Aim 2 will determine the mechanism(s) underlying pro-learning effects of amphetamine, nicotine, and PNU via combined studies with pharmacological inactivation of: 1) a7 nAChRs (methyllycaconitine); 2) dopamine D1-like (SCH 23390); and 3), D2-like receptors (haloperidol); plus 4) Genetic null-mutation of the a7 nAChR, and 5) Adeno- Associated Viral (AAV)-induced suppression of striatal dopamine D1 receptors. Thus, using complementary techniques, we will confirm that a7 nAChR activation improves learning via enhancing reward-associative learning, a mechanism that is a7 nAChR-dependent and that occurs as a result of indirect activation of striatal dopamine D1 receptors. Pro-learning treatments identified here could be tested in healthy humans, potentially augmenting psychotherapeutic interventions and improving the lives of patients with mental illness.

描述（申请人提供）：对于患有严重精神疾病的人来说，认知缺陷是其独立生活的核心障碍。迫切需要改善认知的治疗方法，但十多年来没有新的药物疗法获得批准。心理治疗干预仍然有帮助，但效果有限。由于这些干预措施主要通过积极强化策略来帮助学习，因此通过药物疗法增强此类学习应该可以协同提高这些干预措施的有效性。纹状体多巴胺 D1 受体有助于积极强化学习，但直接针对这些受体会产生不良副作用。激活 a7 烟碱乙酰胆碱受体 (nAChR) 会间接激活纹状体多巴胺 D1 受体，从而在 a7 nAChR 和正向强化学习之间建立联系。该项目将确定多巴胺能和 nAChR 促进学习的治疗方法，并确定它们的作用是否由纹状体多巴胺 D1 受体介导。与奖励和惩罚相关的学习将使用概率学习（PL）任务来衡量。 PL 任务奖励和惩罚对目标和非目标刺激的反应。选择目标刺激通常会受到奖励（80%），但偶尔会受到惩罚（20%）。对于非目标刺激，奖励/惩罚时间表是相反的。因此，重要的是，PL 任务测量动物在不确定性期间获得意外事件的速度，并根据奖励历史来调节其行为。奖励（获胜-停留）后选择同一侧仅在目标响应后才有益，而失败后的转移仅在分别反映良好奖励和惩罚关联学习的非目标响应后才有益。间接多巴胺激动剂左旋多巴通过增强健康人和帕金森病患者的奖赏联想学习来改善 PL。同样，我们证明安非他明（另一种间接多巴胺激动剂）和尼古丁（一种通用的 nAChR 激动剂）通过增强奖赏联想学习来诱导小鼠 PL 的改善。具体目标 1 将确定苯丙胺、尼古丁和选择性 a7 nAChR 激动剂 PNU 282987 的促进学习剂量，并使用苯丙胺作为阳性对照。具体目标 2 将通过结合研究与药理学失活来确定苯丙胺、尼古丁和 PNU 的促进学习作用的机制： 1) a7 nAChR（甲基利卡乌头碱）； 2) 多巴胺 D1 样 (SCH 23390)； 3)、D2样受体（氟哌啶醇）；加 4) a7 nAChR 基因无效突变，以及 5) 腺相关病毒 (AAV) 诱导的纹状体多巴胺 D1 受体抑制。因此，通过使用补充技术，我们将确认 a7 nAChR 激活通过增强奖赏联想学习来改善学习，这是一种 a7 nAChR 依赖性机制，是纹状体多巴胺 D1 受体间接激活的结果。这里确定的促进学习的治疗方法可以在健康人身上进行测试，有可能增强心理治疗干预并改善精神疾病患者的生活。