Neural control of Reinforcement Learning in SUD

SUD 中强化学习的神经控制

• 批准号: 10431851
• 负责人: Jennifer Zachry
• 金额: $ 3.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10431851
• 关键词: Adaptive Behaviors; Address; Affect; Animals; Aversive Stimulus; Behavior; Behavioral; Brain; Calcium; Cells; Complex; Consumption; Cues; Data; Decision Making; Desire for food; Development; Disease; Dissociation; Drug Exposure; Excision; Family; Fiber; Foundations; Genetic Transcription; Goals; Halorhodopsins; Image; Learning; Left; Link; Literature; Mediating; Morphology; Motivation; Mus; Nature; Negative Reinforcements; Neuronal Plasticity; Neurons; Nucleus Accumbens; Operant Conditioning; Opsin; Optics; Outcome; Patients; Pattern; Performance; Pharmaceutical Preparations; Photometry; Physiological; Play; Population; Positive Reinforcements; Psychological reinforcement; Public Health; Publications; Relapse; Rewards; Role; Shock; Signal Transduction; Stimulus; Substance Use Disorder; Sucrose; Syndrome; System; Techniques; Therapeutic; Thinking; Training; Transgenic Organisms; United States; Wolves; awake; base; behavioral plasticity; behavioral response; calcium indicator; cell type; discrete time; drug induced behavior; drug of abuse; experimental study; goal oriented behavior; in vivo; in vivo calcium imaging; innovation; learned behavior; neuroregulation; non-drug; novel; optogenetics; outcome prediction; preservation; relating to nervous system; response; reward processing; training opportunity

Project Summary/Abstract Substance use disorder (SUD) has proven challenging to effectively treat due to the long-term changes in both behavior and neuronal function that persist long after drug has left the system. Drug-induced changes in neuronal plasticity are particularly important as they can disrupt both drug-associated behaviors as well as adaptive behaviors in basal states, thus necessitating a more comprehensive understanding of how the neuronal populations that underlie this plasticity control basal behaviors as they relate to reward processing and motivation. At the core of value-based decision making and motivation is the nucleus accumbens, which is primarily composed of D1 and D2 medium spiny projection neurons (MSNs) that are thought to have opposing actions on behavior with D1 MSNs promoting reward and D2 MSNs promoting aversion. A large body of work has outlined the transcriptional, physiological, and in vivo encoding alterations in these populations that occur as a result of drug exposure and has linked these alterations to drug seeking and consumption. However, these cellular populations are also integrally involved in learning, selecting, and executing goal-oriented behaviors, and function as a key neural substrate of cue-reward associations for drug and non-drug stimuli. Currently, the precise information that is encoded within these populations, and how they guide adaptive behaviors in different contexts, remains to be definitively elucidated. By combining complex reinforcement tasks that can dissociate behavioral action from stimulus and outcome value with optical approaches for recording and manipulating D1 and D2 MSNs in awake, behaving mice we will define the specific information that is encoded within these cellular populations. In Aim 1, I will utilize fiber photometry calcium imaging to define the temporal signature of D1 and D2 medium spiny neurons (MSNs) during complex behavioral tasks. We hypothesize - based on robust preliminary data - that D1 and D2 MSNs are not simply “rewarding” and “aversive”, but instead encode specific components of learned and executed behavior. In Aim 2, I will utilize optogenetics to manipulate activity in D1 and D2 MSNs respectively during discrete time points to demonstrate the functional importance of these neuronal populations to reinforcement learning. While this proposal encompasses the use of a number of innovative techniques, it is the technical and theoretical training, gained in combining these techniques with complex behavioral tasks, that will provide the foundational expertise and conceptual thinking needed to address larger questions regarding how plastic changes in the brain in response to drug exposure support development of SUD. Together, this proposal will provide an exceptional training opportunity while simultaneously providing foundational evidence for the specific changes that occur within genetically defined neuronal populations in adaptive – and maladaptive – states. Furthermore, these findings can ultimately inform our understanding of how to therapeutically approach treatment of a disorder that hijacks normal adaptive systems.

项目总结/摘要 物质使用障碍（SUD）已被证明具有挑战性，有效地治疗，由于长期的变化，在这两个 行为和神经元功能在药物离开系统后仍长期存在。药物诱导的神经元变化 可塑性是特别重要的，因为它们可以破坏药物相关的行为以及适应性 行为在基础状态，因此有必要更全面地了解如何神经元 作为这种可塑性基础的群体控制着与奖励处理相关的基本行为， 动机基于价值的决策和激励的核心是核心利益， 主要由D1和D2中型多刺投射神经元（MSN）组成，这些神经元被认为具有相反的 D1 MSN促进奖励，D2 MSN促进厌恶。大量的工作 已经概述了这些群体中发生的转录、生理和体内编码改变， 并将这些变化与寻求和消费毒品联系起来。但这些 细胞群体也整体参与学习，选择和执行目标导向的行为， 作为药物和非药物刺激的线索-奖赏关联的关键神经基质发挥作用。目前 这些群体中编码的精确信息，以及它们如何在不同的环境中指导适应性行为。 背景，仍有待明确阐明。通过结合复杂的强化任务， 用光学方法记录和操纵D1的刺激和结果值的行为作用 和D2 MSN在清醒，行为小鼠，我们将定义特定的信息，是编码在这些细胞内， 人口。在目标1中，我将利用纤维光度钙成像来定义D1的时间特征， D2中型多刺神经元（MSN）在复杂的行为任务。我们假设-基于鲁棒性 初步数据-D1和D2 MSN不仅仅是“奖励”和“厌恶”，而是编码特定的 学习和执行行为的组成部分。在目标2中，我将利用光遗传学来操纵D1中的活性 和D2 MSN分别在离散的时间点，以证明这些功能的重要性 神经元群体的强化学习。虽然这项建议包括使用一些 创新技术，它是技术和理论培训，在结合这些技术， 复杂的行为任务，这将提供解决问题所需的基础专业知识和概念思维。 更大的问题是关于大脑中的塑料如何对药物暴露做出反应以支持发展 的SUD。总之，这一建议将提供一个特殊的培训机会，同时提供 发生在遗传定义的神经元群体内的特定变化的基础证据， 适应性状态和适应不良状态。此外，这些发现最终可以帮助我们了解 来治疗一种劫持正常适应系统的疾病。

项目成果

Dopamine signaling in the nucleus accumbens core mediates latent inhibition.

• DOI: 10.1038/s41593-022-01126-1
• 发表时间: 2022-08
• 期刊: NATURE NEUROSCIENCE
• 影响因子: 25
• 作者: Kutlu, Munir Gunes;Zachry, Jennifer E.;Melugin, Patrick R.;Tat, Jennifer;Cajigas, Stephanie;Isiktas, Atagun U.;Patel, Dev D.;Siciliano, Cody A.;Schoenbaum, Geoffrey;Sharpe, Melissa J.;Calipari, Erin S.
• 通讯作者: Calipari, Erin S.