The role of dopaminergic and noradrenergic signaling in exploratory and exploitative behavioral states

多巴胺能和去甲肾上腺素能信号在探索和利用行为状态中的作用

• 批准号: 9789946
• 负责人: Aaron Christopher Koralek
• 金额: $ 12.71万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789946
• 关键词: Affect; Anterior; Basal Ganglia; Behavior; Behavioral; Behavioral Paradigm; Brain; Brain region; Calcium; Cells; Code; Color; Communities; Complex; Computing Methodologies; Corpus striatum structure; Decision Making; Dopamine; Dorsal; Environment; Equilibrium; Functional disorder; Image; Individual; Learning; Martes zibellina; Measures; Mental Health; Mental disorders; Mentors; Methods; Microdialysis; Modeling; Multivariate Analysis; Mus; Neuromodulator; Neurons; Norepinephrine; Obsessive-Compulsive Disorder; Outcome; Pattern; Periodicity; Play; Population; Process; Psychological reinforcement; Research; Rewards; Role; Scanning; Schizophrenia; Signal Transduction; Substantia nigra structure; Supervision; Support System; System; Technical Expertise; Techniques; Technology; Training; Universities; Work; cell cortex; cingulate cortex; dopaminergic neuron; environmental change; experience; experimental study; genetic manipulation; locus ceruleus structure; new therapeutic target; noradrenergic; novel; pars compacta; receptor; relating to nervous system; response; skills; transmission process

Project Summary/Abstract We are constantly faced with the trade-off between exploiting past actions with known outcomes and exploring novel actions whose outcomes may be better. When environmental rewards are stable, it is preferable to perform actions known to be rewarding, but when the environment is changeable, it is adaptive to explore alternatives and revisit actions whose value may have changed. This balance between exploitation and exploration is thought to rely on two interacting systems, namely modulation of corticostriatal circuits by dopaminergic neurons of the substantia nigra pars compacta (SNc), and modulation of anterior cingulate cortex (ACC) processing by noradrenergic neurons of the locus coeruleus (LC). However, little is known about the dynamics of these systems during exploitative and exploratory states, and even less is known about how activity in these systems impacts downstream circuits for action selection. Importantly, the decision processes underlying these behavioral states and the neural systems supporting them are central to the dysfunctions seen in a range of mental illnesses, such as Obsessive-compulsive disorder and Schizophrenia, among others. Here, we propose to explore the ways in which dopaminergic and noradrenergic transmission evolve during exploratory and exploitative behavioral states, and how these alterations impact coding in downstream circuits of the dorsal striatum (DS) and ACC. We begin by developing a behavioral paradigm to capture exploratory and exploitative action selection, using reinforcement learning models to quantify behavior. We will perform calcium imaging during this task to relate activity in dopaminergic neurons in SNc and noradrenergic neurons in LC to action selection, characterizing network states with advanced computational methods, as well as confirming the relationship between cell firing and downstream neuromodulator release with fast-scan cyclic voltammetry and microdialysis. We will then investigate how brief or sustained stimulation of dopaminergic and noradrenergic populations differentially impacts DS and ACC circuits, respectively, with particular focus on receptors tuned to brief (D1/α2) or sustained (D2/α1) changes in neuromodulator levels. This work will be conducted in the vibrant research community at Columbia University under the supervision of Drs. Rui Costa and Stefano Fusi. In additional to technical expertise, both Drs. Costa and Fusi have an impressive track record of successful trainees. The candidate has also assembled a team of expert collaborators, including Dr. Eleanor Simpson, Dr. Julia Sable, and Dr. Darcy Peterka. The entire mentoring team will guide the candidate in technical and professional training. The proposed work also has direct implications for a range of mental disorders, with the potential to identify novel therapeutic targets. Together, the proposed experiments will greatly clarify the role of dopaminergic and noradrenergic circuits in modulating behavioral variability, as well as the neural basis for our ability to balance the exploitation of known behaviors with the discovery of novel, creative responses to an ever-changing environment.

项目总结/摘要 我们经常面临这样的权衡：利用过去的行动， 探索新的行动，其结果可能会更好。当环境回报稳定时， 最好是执行已知的奖励行动，但当环境变化时，它是适应性的， 探索替代方案，重新审视价值可能已经改变的行动。这种剥削和 探索被认为依赖于两个相互作用的系统，即皮质纹状体回路的调节， 多巴胺能神经元的黑质pars延髓（SNc），和调制的前扣带 蓝斑（LC）的去甲肾上腺素能神经元处理皮质（ACC）。然而，人们对 这些系统在剥削和探索状态下的动态，甚至更少有人知道如何 这些系统中的活动影响用于动作选择的下游回路。重要的是，决策过程 这些行为状态的基础和支持它们的神经系统是功能障碍的核心 在一系列精神疾病中可以看到，如强迫症和精神分裂症等。 在这里，我们建议探讨多巴胺能和去甲肾上腺素能传递的方式演变 在探索和剥削行为状态，以及这些变化如何影响编码在下游 我们开始通过开发一个行为范式来捕获 探索性和剥削性的行为选择，使用强化学习模型来量化行为。我们将 在该任务期间进行钙成像，以将SNc和去甲肾上腺素能神经元中的多巴胺能神经元的活动与 LC中的神经元动作选择，用先进的计算方法表征网络状态，以及 作为确认细胞放电和下游神经调质释放之间的关系， 伏安法和微透析法。然后，我们将研究如何短暂或持续刺激多巴胺能和 去甲肾上腺素能群体分别对DS和ACC回路产生不同的影响，特别关注 调节神经调质水平的短暂（D1/α2）或持续（D2/α1）变化的受体。 这项工作将在哥伦比亚大学充满活力的研究界进行， 鲁伊·科斯塔和斯特凡诺·富西医生的监督除了技术专长，科斯塔博士和富西博士 拥有令人印象深刻的成功受训记录。候选人还组建了一个专家小组， 合作者，包括埃莉诺·辛普森博士，朱莉娅·塞布尔博士和达西·彼得卡博士。整个指导 团队将指导候选人进行技术和专业培训。这项工作也有直接 对一系列精神障碍的影响，有可能确定新的治疗靶点。在一起， 所提出的实验将极大地阐明多巴胺能和去甲肾上腺素能回路在调节 行为的可变性，以及我们平衡利用已知行为的能力的神经基础 随着对不断变化的环境的新颖的、创造性的反应的发现。