mPFC Regulation of VTA Dopamine and GABA Neuronal Activity During Flexible Updating of Appetitive and Aversive Associations

mPFC 在灵活更新食欲和厌恶关联过程中对 VTA 多巴胺和 GABA 神经元活动的调节

• 批准号: 10748174
• 负责人: Merridee Justice Lefner
• 金额: $ 6.91万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748174
• 关键词: Affect; Behavior; Behavioral; Behavioral Model; Bipolar Disorder; Calcium; Clozapine; Computer Analysis; Conditioned Stimulus; Cues; Data; Desire for food; Dopamine; Environment; Fiber; Future; Genetic; Impairment; Individual; Learning; Literature; Measures; Medial; Mental Depression; Mental disorders; Methods; Modality; Modeling; Neurons; Obsessive-Compulsive Disorder; Outcome; Oxides; Pathway interactions; Pattern; Period Analysis; Photometry; Prefrontal Cortex; Rattus; Regulation; Research; Rewards; Rodent; Role; Schizophrenia; Shock; Stimulus; Testing; Training; Update; Ventral Tegmental Area; Work; dopaminergic neuron; flexibility; foot; gamma-Aminobutyric Acid; genetic manipulation; neural circuit; optogenetics; outcome prediction; post-doctoral training; response; sugar

Project Summary/Abstract In order to efficiently traverse an environment, one must learn to distinguish among cues that predict outcomes of different modalities, such as an appetitive reward or an aversive shock. In a dynamic environment where cues predicting rewarding or aversive outcomes unexpectedly change, it is adaptive to flexibly update behavioral responding while retaining the ability to recall previous associations. Impairments in the ability to appropriately respond to cues according to the outcome are evident in a number of psychiatric disorders. The overarching aim of my postdoctoral training is to better understand the neural circuitry responsible for updating previously learned cue-outcome associations. A large literature has implicated the ventral tegmental area (VTA) in the initial learning of appetitive and aversive associations. Both dopamine and γ-aminobutyric acid (GABA) neurons in the VTA are involved individually or cooperatively in different aspects of appetitive and aversive learning. After initial learning, I hypothesize that flexible responding to changes in outcome contingencies is modulated by the medial prefrontal cortex (mPFC) projections to the VTA in a valence-specific manner. To behaviorally quantify initial learning as well as updating cue-outcome associations, I will use a flexible contingency learning (FCL) task in which three distinct cues are paired with either an appetitive outcome (sugar pellet reward), an aversive outcome (mild foot shock), or no outcome. After learning, the appetitive and aversive outcomes reverse such that the cue previously paired with a shock will instead precede reward delivery and vice versa. I will be trained in fiber photometry recordings from VTA dopamine and GABA neurons as well as chemogenetic manipulation of the mPFC-VTA pathway to test whether the mPFC regulates flexible updating in a valence-specific manner. Regardless of the outcome, the proposed work will increase our understanding of the flexible updating of behavioral responding when outcome contingencies change.

项目概要/摘要 为了有效地穿越一个环境，人们必须学会区分预测的线索 不同方式的结果，例如动态环境中的食欲奖励或厌恶冲击。 当预测奖励或厌恶结果的线索意外改变时，它可以自适应地灵活更新 行为反应，同时保留回忆先前联想的能力。 根据结果​​对提示做出适当的反应在许多精神疾病中都很明显。 我博士后培训的首要目标是更好地理解负责更新的神经回路 之前学到的线索-结果关联。 大量文献表明腹侧被盖区（VTA）与食欲和食欲的初始学习有关。 VTA 中的多巴胺和 γ-氨基丁酸 (GABA) 神经元都参与其中。 在初步学习之后，我可以单独或合作地进行食欲和厌恶学习的不同方面。 因此，对意外结果变化的灵活反应是由内侧调节的 前额皮质 (mPFC) 以特定价态方式对 VTA 进行预测，以行为方式量化初始值。 学习以及更新提示结果关联，我将使用灵活的应急学习（FCL）任务 这三种不同的线索与食欲结果（糖丸奖励）、厌恶结果配对 学习后，食欲和厌恶结果会逆转这种情况。 之前与电击配对的提示将在奖励交付之前进行，反之亦然。 VTA 多巴胺和 GABA 神经元的纤维光度记录以及化学遗传学操作 mPFC-VTA 通路的研究，以测试 mPFC 是否以价态特异性方式调节灵活更新。 无论结果如何，拟议的工作将增加我们对灵活更新的理解 当结果发生变化时的行为反应。