Plasticity and Function of Dopamine Circuits Regulating the Transition to Habit

项目总结/摘要 习惯和运动技能对于生存至关重要，可以快速，流畅和自动执行动作 这些方法都被反复证明是有益的。尽管它们很有用，但习惯和运动技能是有代价的： 行为灵活性以前有益的自动化行动可能会变得不适应，如果行动- 结果的偶然性会改变。因为自动化操作一旦建立就很难调整， 行为可以持续，正如假设发生在强迫症（OCD）和成瘾中， example.我的实验室的一个主要长期目标是了解行为是如何以及为什么变得自动化的 通过习惯形成和运动技能获得的密切相关过程。正常的流程是什么 以及它在精神疾病中是如何出错的？以前的研究已经确定了一个关键作用， 背外侧纹状体（DLS），但目前尚不清楚DLS如何随着时间的推移参与行为， 目标导向的动作被重复和自动化。现有的理论很难进行实证检验， 外地该项目利用了神经回路跟踪的最新技术进步， 细胞类型的交叉遗传靶向，光遗传学和纤维光度学，创新地结合， 带来新的数据来解决这个问题，并激发对新假设的研究。我们的主要目标是 一项建议是描述控制多巴胺能输入DLS的神经回路，这对DLS的研究至关重要。 调节这个大脑区域的突触可塑性。我们将确定突触可塑性机制 与习惯形成和运动技能相关的DLS多巴胺释放变化的多巴胺能中脑 收购，并实证检验一个长期存在的假设在该领域，上升螺旋假说， 假设纹状体目标导向区域的活动会抑制DLS多巴胺的释放。我们将重新制定 根据新的数据，根据需要提出螺旋上升假说。我们的创新方法集成了电路 追踪、电生理学、光遗传学、纤维光度学和行为研究，三个特定目标， 跨越从详细的亚细胞突触输入映射到体内电路功能的分析水平。与 这个项目的成功完成，我们将提供一个强大的表征上升螺旋电路， 它在控制DLS多巴胺动力学之前，期间和之后的行动自动化的作用。这项研究将 具有广泛的影响，因为它将回答有关行动背后的神经机制的基本问题 自动化.通过了解大脑回路的活动，从目标导向的控制过渡到习惯 和运动技能，我们将打开一个新的切入点，研究复杂的多基因疾病，如强迫症， 而成瘾则是遗传和环境因素共同作用于神经回路功能的结果。

PROJECT SUMMARY/ABSTRACT Habits and motor skills are essential to survival, allowing for the fast, fluid, and automatic execution of actions that have repeatedly proved beneficial. Despite their utility, habits and motor skills come at a cost: a loss of behavioral flexibility. Automated actions that were previously beneficial can become maladaptive if action- outcome contingencies shift. Because automated actions are hard to adjust once established, maladaptive behaviors can persist, as is hypothesized to occur in obsessive-compulsive disorder (OCD) and addiction, for example. A major long-term goal of my laboratory is to understand how and why actions become automated through the closely related processes of habit formation and motor skill acquisition. What is the normal process of automation and how may it go awry in psychiatric disorders? Previous studies have identified a key role for the dorsolateral striatum (DLS), but it remains unclear how the DLS becomes engaged in behavior over time as goal-directed actions are repeated and automated. Existing theories have been difficult to test empirically, stalling the field. This project takes advantage of recent technological advancements in neural circuit tracing, intersectional genetic targeting of cell types, and optogenetics and fiber photometry, innovatively combined, to bring new data to bear on the problem and to inspire work on fresh hypotheses. Our main objective in this proposal is to characterize the neural circuits controlling dopaminergic input to the DLS, which is critical for regulating synaptic plasticity in this brain region. We will identify synaptic plasticity mechanisms in the dopaminergic midbrain that underlie changes in DLS dopamine release related to habit formation and motor skill acquisition, and empirically test a long-standing hypothesis in the field, the Ascending Spiral Hypothesis, which posits that activity in goal-directed regions of the striatum disinhibits DLS dopamine release. We will reformulate the Ascending Spiral Hypothesis as needed based on new data. Our innovative approach integrates circuit tracing, electrophysiology, optogenetics, fiber photometry, and behavioral studies across three specific aims, spanning levels of analysis from detailed subcellular synaptic input mapping to in vivo circuit function. With the successful completion of this project, we will provide a robust characterization of the Ascending Spiral circuit and its role in controlling DLS dopamine dynamics before, during, and after action automation. This research will have a broad impact as it will answer fundamental questions about the neural mechanisms underlying action automation. By understanding the brain circuit activity allowing transitions from goal-directed control to habits and motor skills, we will unlock a new point of entry into studying how complex polygenic diseases such as OCD and addiction emerge from the confluence of genetic and environmental factors on circuit function.