Co-Regulation of Striatal Dopamine and Acetylcholine During Flexible Learning

灵活学习期间纹状体多巴胺和乙酰胆碱的共同调节

• 批准号: 10296417
• 负责人: Christoph Kellendonk
• 金额: $ 57.71万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296417
• 关键词: Acetylcholine; Acute; Affect; Animals; Attenuated; Behavior; Behavioral; Brain; Brain Diseases; Code; Cognitive; Computer Models; Corpus striatum structure; Cues; DRD2 gene; Data; Disease; Dopamine; Dopamine D2 Receptor; Educational process of instructing; Electrophysiology (science); Event; Functional disorder; Generations; Impaired cognition; Impairment; Incidence; Interneuron function; Interneurons; Learning; Length; Lesion; Measures; Mediating; Mental disorders; Mus; Neuromodulator; Neurons; Neurotransmitters; Outcome; Oxidopamine; Parkinson Disease; Patients; Performance; Pharmaceutical Preparations; Pharmacology; Physiology; Play; Primates; Regulation; Reversal Learning; Rewards; Role; Schizophrenia; Signal Transduction; Slice; Stimulus; System; Testing; Thalamic structure; Therapeutic; Time; Up-Regulation; acetylcholine transporter; base; behavior measurement; cholinergic; clinically relevant; dopaminergic neuron; flexibility; gain of function; in vivo; insight; learned behavior; nonhuman primate; novel therapeutics; optogenetics; response; sensor; temporal measurement; tool

Project Summary The neuromodulators acetylcholine (ACh) and dopamine (DA) play important roles in learning. In the striatum cholinergic interneurons (CINs) are modulated co-incident with the release of DA in response to unpredicted rewards and reward predicting cues and both signals have been implicated in coding prediction error signals. Whereas DA neurons are mostly activated by these salient events, CINs often show a multiphasic response with a prominent pause in activity. The time locked occurrence of both signals suggest that they are coordinated but it is still unclear whether they are regulated independently from each other or whether they mutually regulate each other. Moreover, whether their temporal co-incidence is important for learning still needs to be determined. Support for a mutual co-regulation comes from both stimulation and lesion studies. In the slice, DA released from DA terminals inhibits the activity of CINs via activation of D2 receptors. Strikingly, classical 6-OHDA lesion studies in non-human primates suggest that the pause in Tonically Active Neurons (TANs), the primate counterparts of CINs, is fully dependent on DA; although this hypothesis has been challenged by data implicating thalamic or other projections in the pause generation. Slice physiology and in vivo stimulations studies have further shown that ACh released from CINs locally induces DA release. One limitation of stimulation studies is that they do not measure naturally evoked ACh or DA levels. Thus, the importance of this mutual co-regulation during learning must be determined under natural conditions. An ideal way to achieve this is to simultaneously measure behaviorally-evoked changes in DA and ACh levels in the same animal. Since striatal ACh has been found to be important when behavior needs to be adapted to new task rules the application will focus on understanding the importance of the mutual co-regulation of DA and ACh for cognitive flexibility. To this end, we propose to simultaneously record task-evoked DA and ACh transients in the mouse during two flexible learning behaviors, Go/NoGo and reversal learning. Our preliminary data show that both behaviors are affected by striatal CIN function. We then will isolate the DA-dependent component of the ACh signal by enhancing or abolishing the ability of DA to inhibit CINs. Conversely, we will abolish the ability of CINs to release ACh or inhibit CIN activity with high temporal resolution. Determining how these manipulations affect task-evoked changes in ACh/DA levels and performance will establish the importance of mutual co-regulation of DA and ACh signals for flexible learning. Our studies will provide mechanistic insights into DA and ACh co-regulation in the striatum. This has clinical relevance as both neurotransmitters are dysregulated in the striatum of patients with brain disorders including schizophrenia and Parkinson disorder, where both neuromodulator systems are targeted by current therapeutic treatments.

项目摘要 神经调节剂乙酰胆碱（ACH）和多巴胺（DA）在学习中起重要作用。在纹状体中 胆碱能中间神经元（CINS）与不预测的DA释放有关 奖励和奖励预测提示和两个信号都与编码预测错误信号有关。 尽管DA神经元主要被这些显着事件激活，而CIN经常显示出多相反应 活动的突出停顿。两个信号的时间锁定发生表明它们是协调的，但是 目前尚不清楚它们是否彼此独立地调节或是否相互调节 彼此。此外，仍然需要确定它们的时间共同关系对于学习是否重要。 对相互共同调节的支持来自刺激和病变研究。在切片中，da从 DA末端通过激活D2受体抑制CIN的活性。令人惊讶的是古典的6-OHDA病变 非人类灵长类动物的研究表明，在灵长类 CINS的对应物完全取决于DA。尽管该假设受到涉及的数据的挑战 暂停一代中的丘脑或其他预测。切片生理学和体内刺激研究具有 进一步表明，从CINS释放的ACH诱导DA释放。刺激研究的一个局限性是 他们不会衡量自然诱发的ACH或DA级别。因此，这种相互共同调节的重要性 在学习过程中必须在自然条件下确定。实现这一目标的理想方法是同时 测量同一动物中DA和ACH水平的行为引起的变化。由于纹状体ACH一直 当需要适应新任务规则时，发现该应用程序将重点关注的行为很重要 了解DA和ACH相互共同调节对认知灵活性的重要性。为此，我们 提议在两个灵活的学习过程中同时记录鼠标中的任务引起的DA和ACH瞬变 行为，nogo/nogo和逆转学习。我们的初步数据表明，这两种行为都受纹状体的影响 CIN功能。然后，我们将通过增强或废除来隔离ACH信号的DA依赖性成分 DA抑制CIN的能力。相反，我们将废除CIN释放ACH或抑制CIN的能力 具有高时间分辨率的活动。确定这些操作如何影响任务引起的变化 ACH/DA级别和性能将确定DA和ACH信号相互共同调节的重要性 灵活的学习。我们的研究将提供对纹状体中DA和ACH共同调节的机械见解。 这具有临床相关性，因为两个神经递质在脑纹状体中均失调 精神分裂症和帕金森氏症在内 当前的治疗疗法。