Co-Regulation of Striatal Dopamine and Acetylcholine During Flexible Learning

灵活学习过程中纹状体多巴胺和乙酰胆碱的共同调节

基本信息

批准号：
10453579
负责人：
Christoph Kellendonk
金额：
$ 53.4万
依托单位：
NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
依托单位国家：
美国
项目类别：
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/10453579
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

项目摘要

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.

项目概要神经调节剂乙酰胆碱（ACh）和多巴胺（DA）在学习中发挥着重要作用。在纹状体中胆碱能中间神经元 (CIN) 的调节与 DA 的释放同时发生，以应对不可预测的情况奖励和奖励预测线索，这两个信号都与编码预测误差信号有关。虽然 DA 神经元主要由这些显着事件激活，但 CIN 经常表现出多相反应活动明显暂停。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相互独立监管还是相互监管彼此。此外，它们的时间重合对于学习是否重要仍然需要确定。对相互共同调节的支持来自刺激和损伤研究。在切片中，DA 释放自 DA 末端通过激活 D2 受体抑制 CIN 的活性。引人注目的是，经典的 6-OHDA 损伤对非人类灵长类动物的研究表明，灵长类动物的紧张性活跃神经元（TAN）的暂停 CIN 的对应部分，完全依赖于 DA；尽管这一假设受到了涉及数据的挑战丘脑或暂停生成中的其他投射。切片生理学和体内刺激研究进一步表明，CIN 释放的 ACh 局部诱导 DA 释放。刺激研究的局限性之一是他们不测量自然诱发的 ACh 或 DA 水平。因此，这种相互共同监管的重要性学习时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行为诱发的 DA 和 ACh 水平变化。由于纹状体 ACh 已当行为需要适应应用程序将关注的新任务规则时，发现很重要了解 DA 和 ACh 相互共同调节对于认知灵活性的重要性。为此，我们建议在两个灵活的学习过程中同时记录小鼠中任务诱发的 DA 和 ACh 瞬态行为、Go/NoGo 和逆转学习。我们的初步数据表明，这两种行为都受到纹状体的影响 CIN 功能。然后，我们将通过增强或消除 ACh 信号的 DA 依赖性成分来分离 DA 抑制 CIN 的能力。反之，我们将废除CINs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 水平和性能将确定 DA 和 ACh 信号相互共同调节的重要性灵活学习。我们的研究将为纹状体中 DA 和 ACh 的共同调节提供机制见解。这具有临床意义，因为这两种神经递质在脑部疾病患者的纹状体中失调。包括精神分裂症和帕金森病在内的疾病，其中两种神经调节系统都是目前的治疗方法。