Alpha 7 nicotinic receptor-mediated enhancement of reinforcement learning

描述（由申请人提供）：对于患有严重精神疾病的人来说，认知缺陷是他们独立生活的核心障碍。改善认知的治疗方法是迫切需要的，但十多年来没有新的药物治疗方法被批准。心理治疗干预仍然有帮助，但仅表现出适度的效果。由于这些干预措施主要通过积极强化策略来帮助学习，因此通过药物治疗来增加这种学习应该协同提高这些干预措施的有效性。纹状体多巴胺D1受体有助于正强化学习，但直接针对这些受体产生不良的副作用。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，提供a7 nAChR与正强化学习之间的联系。本项目将确定多巴胺能和nAChR对学习的促进作用，并确定它们的作用是否由纹状体多巴胺D1受体介导。奖惩相关学习将使用概率学习（PL）任务进行测量。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得到奖励（80%），但偶尔会受到惩罚（20%）。对于非目标刺激，奖惩时间表是相反的。因此，重要的是，PL任务测量动物在不确定性中获得偶然性的速度，并将其行为调节为奖励历史的函数。在获得奖励后选择同一边（赢-留）只有在目标反应后才有益，而在失去奖励后选择同一边只有在非目标反应后才有益，而非目标反应分别反映了良好的奖惩联想学习。间接多巴胺激动剂左旋多巴通过增强健康人和帕金森患者的奖励联想学习来改善PL。同样，我们证明了安非他明（另一种间接多巴胺激动剂）和尼古丁（一种通用的nAChR激动剂）通过增强奖励联想学习诱导小鼠PL的改善。特异性目标1将确定安非他明、尼古丁和选择性a7 nAChR激动剂PNU 282987的促进学习剂量，以安非他明为阳性对照。特异性目标2将通过联合研究确定安非他明、尼古丁和PNU促进学习作用的机制，并对以下因素进行药理学灭活：1)a7 nAChRs（甲基莱卡乌碱）；2)多巴胺d1样（SCH 23390）；3) d2样受体（氟哌啶醇）；4) a7 nAChR基因零突变，5)腺相关病毒（AAV）诱导纹状体多巴胺D1受体抑制。因此，使用互补技术，我们将证实a7 nAChR激活通过增强奖励联想学习来改善学习，这是一种依赖于a7 nAChR的机制，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，可能会增加心理治疗干预措施，改善精神疾病患者的生活。

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.