Plasticity and Function of Dopamine Circuits Regulating the Transition to Habit

多巴胺回路的可塑性和功能调节习惯的转变

• 批准号: 10743544
• 负责人: Talia Newcombe Lerner
• 金额: $ 50.27万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-16 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743544
• 关键词: Address; Anatomy; Area; Automation; Behavior; Behavioral; Brain; Brain region; Cells; Complex; Corpus striatum structure; Data; Dendrites; Dependence; Disease; Disinhibition; Distal; Dopamine; Electrophysiology (science); Environmental Risk Factor; Excitatory Synapse; Fiber; Formulation; Foundations; Functional disorder; Future; Genetic; Goals; Habits; Individual; Influentials; Laboratories; Learning; Lighting; Liquid substance; Location; Long-Term Potentiation; Maps; Measures; Mental disorders; Midbrain structure; Modeling; Monkeys; Motor Skills; Mus; Neurobiology; Neurons; Neurosciences; Obsessive-Compulsive Disorder; Outcome; Pacemakers; Pattern; Photometry; Positioning Attribute; Process; Property; Regulation; Research; Research Personnel; Response to stimulus physiology; Rest; Rewards; Role; Slice; Solid; Source; Substantia nigra structure; Symptoms; Synapses; Synaptic plasticity; Technical Expertise; Technology; Testing; Time; Training; Work; addiction; adverse outcome; behavioral response; behavioral study; candidate identification; cell type; compulsion; cost; dopaminergic neuron; experimental study; field study; flexibility; in vivo; innovation; maladaptive behavior; motivated behavior; neural circuit; neuromechanism; neuropsychiatric disorder; optogenetics; recruit; repetitive behavior; skill acquisition; skills training; theories

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.

项目摘要/摘要 习惯和运动技能对于生存至关重要，可以快速，流动和自动执行动作 一再被证明是有益的。尽管它们的实用性，但习惯和运动技能是有代价的：损失 行为灵活性。如果采取行动 结果突发事件发生了变化。因为一旦建立自动化的动作就难以调整，所以适应不良 行为可以持续存在，这是在强迫症（OCD）和成瘾中发生的，因为 例子。我实验室的一个主要长期目标是了解行动如何以及为什么自动化 通过与习惯形成和运动技能采取的紧密相关的过程。什么是正常过程 自动化以及如何在精神疾病中出现问题？先前的研究已经确定了 背外侧纹状体（DLS），但尚不清楚DLS如何随着时间的推移从事行为 重复和自动化目标指导的动作。现有理论很难经验测试，停滞不前 领域。该项目利用了神经电路追踪中的最新技术进步， 细胞类型的交叉遗传靶向，以及创新合并的光遗传学和光纤光度法 携带新的数据来解决问题，并激发有关新假设的工作。我们的主要目标 建议是表征控制DLS多巴胺能输入的神经回路，这对于 调节该大脑区域的突触可塑性。我们将确定突触可塑性机制 多巴胺能中脑的DLS多巴胺释放的基础与习惯形成和运动技能有关 获取，并在经验上检验该领域的长期假设，即上升的螺旋假设，该假设 假定纹状体的目标定向区域的活性抑制了DLS多巴胺的释放。我们将重新重构 根据新数据，根据需要根据需要进行上升螺旋假设。我们的创新方法整合了电路 探针，电生理学，光遗传学，纤维光度法和行为研究三个特定目标， 从详细的亚细胞突触输入映射到体内电路函数的分析水平。与 成功完成了该项目，我们将提供升上螺旋电路的强大特征， 它在动作自动化之前，之中和之后控制DLS多巴胺动力学方面的作用。这项研究会 具有广泛的影响，因为它将回答有关神经机制的基本问题 自动化。通过了解大脑电路活动，允许从目标指导控制到习惯的过渡 和运动技能，我们将解锁一个新的入境点，以研究OCD等复杂多基因疾病 从遗传和环境因素的汇合处出现了成瘾。