Alpha 7 nicotinic receptor-mediated enhancement of reinforcement learning

描述（由申请人提供）：对于那些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，但只有中等效果。由于这些干预措施主要是通过积极强化策略来帮助学习，因此用药物治疗来增强这种学习应该会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，但直接靶向这些受体会产生不良副作用。激活α 7烟碱乙酰胆碱受体（nAChR）间接激活纹状体多巴胺D1受体，提供了α 7 nAChR和正强化学习之间的联系。该项目将确定多巴胺能和nAChR促学习治疗，并确定其效果是否由纹状体多巴胺D1受体介导。奖励和惩罚相关的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，奖励/惩罚时间表是颠倒的。因此，重要的是，PL任务测量了动物在不确定性期间获得突发事件的速度，并将其行为作为奖励历史的函数进行调节。奖励后选择同一侧（赢-留）只有在目标反应后才是有益的，而损失后转移只有在非目标反应后才是有益的，分别反映了良好的奖励和惩罚联想学习。间接多巴胺激动剂左旋多巴通过增强健康人和帕金森病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（一般nAChR激动剂）通过增强奖励联想学习诱导小鼠PL的改善。 具体目标1将确定安非他明、尼古丁和选择性α 7 nAChR激动剂PNU 282987的促学习剂量，使用安非他明作为阳性对照。具体目标2将通过联合研究确定安非他明、尼古丁和PNU的促学习作用的潜在机制，包括药理学失活：1）α 7 nAChR（甲基可可碱）; 2）多巴胺D1样（SCH 23390）;和3），D2样受体（氟哌啶醇）;加上4）α 7 nAChR的遗传零突变，和5）腺相关病毒（AAV）诱导的纹状体多巴胺D1受体抑制。因此，使用补充技术，我们将证实，α 7 nAChR激活通过增强奖励联想学习，一种机制，是α 7 nAChR依赖性的，并发生作为纹状体多巴胺D1受体的间接激活的结果，提高学习。这里确定的亲学习疗法可以在健康人群中进行测试，有可能增强心理治疗干预，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.