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

项目摘要/摘要(家长资助) 我们经常面临着利用过去已知结果的行动和利用已知结果之间的权衡 探索结果可能更好的新奇行动。当环境回报是稳定的时，它是 更好地执行已知有益的行为，但当环境变化时，它可以适应 探索替代方案，并重新审视其价值可能已改变的行动。剥削和剥削之间的这种平衡 探索被认为依赖于两个相互作用的系统，即通过 黑质致密部多巴胺能神经元与前扣带回的调制 蓝斑(LC)去甲肾上腺素能神经元对皮层(ACC)的处理。然而，人们对此知之甚少。 这些系统在剥削和探索状态下的动态，更不清楚它们是如何 这些系统中的活动影响用于动作选择的下游电路。重要的是，决策过程 在这些行为状态和支持它们的神经系统之下，是功能障碍的中心 出现在一系列精神疾病中，如强迫症和精神分裂症等。 在这里，我们建议探索多巴胺能和去甲肾上腺素能传递进化的方式。 在探索性和剥削性行为状态期间，以及这些更改如何影响下游的编码 背侧纹状体(DS)和ACC的环路。我们首先开发一种行为范式来捕获 探索性和剥削性行为选择，使用强化学习模型对行为进行量化。我们会 在这项任务中进行钙成像，以关联黑质和去甲肾上腺素能多巴胺能神经元的活动 LC中的神经元对动作选择，也用先进的计算方法表征网络状态 应用快速扫描循环证实细胞放电与下游神经递质释放的关系 伏安法和微渗析。然后我们将研究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 受体调节为神经调节剂水平的短暂变化(D1/α2)或持续变化(D2/α1)。 这项工作将在哥伦比亚大学充满活力的研究社区进行， Rui Costa博士和Stefano Fusi博士的监督。除了技术专长，科斯塔博士和福斯博士 有令人印象深刻的成功实习生的记录。候选人还组建了一支专家团队 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。整个辅导过程 团队将指导应聘者进行技术和专业培训。建议的工作也有直接的 对一系列精神障碍的影响，有可能确定新的治疗靶点。一起， 拟议中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制中的作用。 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、创造性的反应的发现。

Project Summary/Abstract (parent grant) 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.