Using large scale electrophysiology to study the role of midbrain dopamine neurons underlying motivated behaviors

利用大规模电生理学研究中脑多巴胺神经元在动机行为背后的作用

• 批准号: 10460969
• 负责人: Kurt M Fraser
• 金额: $ 7.22万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460969
• 关键词: Action Potentials; Amygdaloid structure; Anatomy; Animals; Area; Aversive Stimulus; Basal Ganglia; Behavior; Behavior Control; Behavioral; Calcium; Complex; Cues; Desire for food; Development; Disease; Dissociation; Drug usage; Electrophysiology (science); Event; Failure; Fiber; Foundations; Future; Generations; Globus Pallidus; Glutamates; Goals; Health; Heterogeneity; Human; Image; Intervention; Investigation; Lateral; Learning; Medial; Mental disorders; Midbrain structure; Motivation; Mus; Neurons; Outcome; Pharmaceutical Preparations; Photometry; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Prefrontal Cortex; Prosencephalon; Regulation; Relapse; Research; Resolution; Rewards; Role; Running; Signal Transduction; Source; Stimulus; Substance Use Disorder; Support System; Technical Expertise; Techniques; Testing; Therapeutic Intervention; Time; Training; Translating; Ventral Striatum; Ventral Tegmental Area; base; behavior influence; behavioral response; cell type; craving; dopamine system; dopaminergic neuron; expectation; flexibility; gamma-Aminobutyric Acid; in vivo; motivated behavior; novel; optogenetics; relating to nervous system; response; skills

PROJECT SUMMARY A core feature of a number of psychiatric illnesses is the disordered estimation of the predictive relationship between a given cue and an outcome. This failure to appraise and generate appropriate behavioral responses is true for cues that both are rewarding and aversive. For example, in post-traumatic stress disorders innocuous stimuli can elicit intense aversive motivational responses even though these were encountered in a safe and familiar context. On the other hand, in substance use disorders previously drug-paired cues can elicit intense craving and trigger relapse, despite these cues being encountered in settings where drug use never occurred. As a result, it is critical to understand the factors and neural systems that support and regulate cue-triggered motivations in the hope of identifying potential treatments for disorders of motivation. Dopamine neurons within the ventral tegmental area (VTA) are well known to be responsible for reward-related learning, yet subsets of VTA dopamine neurons are excited by aversive stimuli which opposes an exclusive role for these neurons in reward. However, there is limited understanding of how such heterogeneity in VTA dopamine neurons contributes to the dynamic control of reward and aversion as these are primarily assessed in conditions where animals learn cue-outcome associations that are rigid and stable which occlude the ability to differentiate the encoding of value and valence. Here, I propose a novel behavioral approach that dynamically alters the relations between cues and either rewarding or aversive outcomes on a trial-to-trial basis to understand the contribution of VTA dopamine neurons to the flexible generation of motivated behaviors. This behavioral approach will allow me to test whether defined subsets of VTA dopamine neurons encode the long-running learned value versus the immediate motivational significance of cues that are otherwise ambiguously rewarding or aversive which has important implications for our understandings of these neurons in health and disease. The primary goals are to (1) apply a large-scale electrophysiological approach to detail correlates of reward and aversion in projection- defined VTA dopamine neurons, (2) assess the contribution of distinct VTA dopamine neurons to the flexible control of reward and aversion, and (3) detail the computations supported by ventral basal ganglia inputs onto VTA dopamine neurons that make possible the generation of flexible motivated behavior. Collectively the proposed research provides me extensive training that translates my skills into mice, integrates optogenetics with large-scale recording approaches, and develops an approach for the recording of neurons in a cell-type and circuit-defined manner during complex behaviors. Deconstructing the function of VTA dopamine neurons in the rapid regulation of reward and aversion is a significant step in our understanding of the contributions of these neurons in psychiatric illness and has potential for generating novel interventions and therapies.

项目摘要 许多精神疾病的核心特征是对预测关系的无序估计 和结果之间的联系这种未能评估和产生适当的行为反应 对于奖励和厌恶的线索都成立例如，在创伤后应激障碍中 刺激可以引起强烈的厌恶性动机反应，即使这些是在一个安全的， 熟悉的背景。另一方面，在物质使用障碍中，先前的药物配对线索可以引起强烈的 尽管这些线索是在从未使用过毒品的环境中遇到的。 因此，了解支持和调节线索触发的因素和神经系统至关重要 动机，希望找到潜在的治疗动机障碍的方法。内多巴胺神经元 腹侧被盖区（ventral tegmental area，VTA）是一个负责奖赏相关学习区域， 腹侧被盖区多巴胺神经元被厌恶性刺激所兴奋，这与这些神经元在脑内的排他性作用相反。 奖励然而，对于腹侧被盖区多巴胺神经元中的这种异质性， 有助于奖励和厌恶的动态控制，因为这些主要是在以下条件下评估的， 动物学习的线索-结果关联是刚性和稳定的，这阻碍了区分 价值和效价的编码。在这里，我提出了一种新的行为方法，动态地改变关系， 在一次又一次试验的基础上，了解线索与奖励或厌恶结果之间的关系， 腹侧被盖区多巴胺神经元对灵活产生动机性行为的作用。这种行为方法将允许 我来测试是否定义的腹侧被盖区多巴胺神经元的子集编码长期运行的学习值与 暗示的直接激励意义，否则是模棱两可的奖励或厌恶，这已经 对我们理解这些神经元在健康和疾病中的作用有重要意义。主要目标是 (1)应用大规模的电生理学方法来研究投射中奖励和厌恶的细节相关性- 定义的腹侧被盖区多巴胺神经元，（2）评估不同的腹侧被盖区多巴胺神经元对灵活的 控制奖励和厌恶，（3）详细说明腹侧基底神经节输入支持的计算， 腹侧被盖区的多巴胺神经元，使灵活的动机行为的产生成为可能。统称 拟议中的研究为我提供了广泛的培训，将我的技能转化为小鼠，整合光遗传学， 与大规模的记录方法，并开发了一种方法，用于记录神经元的细胞类型， 在复杂的行为过程中，电路定义的方式。腹侧被盖区多巴胺神经元功能的解构 对奖赏和厌恶的快速调节是我们理解这些因素的重要一步。 神经元在精神疾病中的作用，并有可能产生新的干预措施和疗法。