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（由申请人提供）：对于患有严重精神疾病的人，认知缺陷是他们独立生活的核心障碍。迫切需要迫切需要改善认知的治疗方法，但是十多年来，没有批准新的药物治疗。心理治疗干预措施仍然有用，但仅表现出适度的效果大小。因为这些干预措施主要通过积极的加强策略来帮助学习，因此通过药物治疗来增强这种学习应协同增强这些干预措施的有效性。纹状体多巴胺D1受体有助于阳性增强学习，但直接靶向这些受体会产生不良的副作用。激活A7烟碱乙酰胆碱受体（NACHR）间接激活纹状体多巴胺D1受体，从而在A7 NACHR和阳性增强学习之间提供了联系。该项目将鉴定多巴胺能和NACHR促学习治疗方法，并确定其作用是否是由纹状体多巴胺D1受体介导的。将使用概率学习（PL）任务来衡量奖励和惩罚与相关学习。 PL任务奖励和惩罚对目标和非目标刺激的反应。通常会奖励目标刺激（80％），但偶尔会受到惩罚（20％）。对于非目标刺激，奖励/惩罚时间表被颠倒了。因此，重要的是，PL任务衡量动物在不确定性期间获得突发事件的速度，并将其行为调节作为奖励历史的函数。仅在目标响应之后选择奖励后选择同一方面才是有益的，而在损失后进行损失的转移才有有益，只有在反映出良好的奖励和惩罚 - 和社会学习的学习后才有益。间接多巴胺激动剂左旋多巴通过增强健康人和帕金森氏病患者的奖励促进学习来改善PL。同样，我们证明了苯丙胺（另一种间接多巴胺激动剂）和尼古丁 - （一种普通的NACHR激动剂）通过增强奖励 - 社会学习而诱导了小鼠PL的改善。特定的目标1将鉴定苯丙胺，尼古丁和选择性A7 NACHR激动剂PNU 282987，利用苯丙胺作为阳性对照。具体的目标2将通过与药理学失活的联合研究（1）A7 NACHRS（甲基乙二醇）（甲基乙二醇）的结合研究来确定苯丙胺，尼古丁和PNU的潜在促进学习作用的机制； 2）多巴胺D1样（SCH 23390）;和3），D2样受体（氟哌啶醇）；加4）A7 NACHR的遗传无效和5）腺相关病毒（AAV）诱导的纹状体多巴胺D1受体的抑制。因此，使用互补技术，我们将确认A7 NACHR激活通过增强奖励 - 社会学习来改善学习，该机制是A7 NACHR依赖性的，并且由于纹状体多巴胺D1受体的间接激活而发生。可以在健康的人类中测试此处确定的亲学习治疗方法，可能会增加心理治疗干预措施并改善精神疾病患者的生活。