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.

项目总结/摘要 为了有效地穿越环境，必须学会区分预测的线索 结果的不同形式，如食欲奖励或厌恶冲击。在动态环境中 当预测奖励或厌恶结果的线索发生意外变化时， 行为反应，同时保留回忆以前关联的能力。能力的损害， 根据结果对线索作出适当反应在许多精神疾病中是显而易见的。的 我的博士后培训的首要目标是更好地了解负责更新的神经回路 先前学习的线索-结果关联。 大量的文献表明腹侧被盖区（VTA）参与了食欲的初始学习， 令人厌恶的联想腹侧被盖区的多巴胺和γ-氨基丁酸（GABA）神经元都参与了 个体或合作在不同方面的食欲和厌恶的学习。经过初步学习，我 假设对结果偶然性变化的灵活反应是由中介调节的， 前额叶皮层（mPFC）的预测，腹侧被盖区在一个价特异性的方式。从行为上量化初始 学习以及更新线索-结果关联，我将使用灵活的权变学习（FCL）任务， 这三种不同的暗示与食欲结果（糖丸奖励）、厌恶结果相结合 结局（轻度足休克）或无结局。在学习之后，欲望和厌恶的结果会逆转这种情况。 先前与电击配对的提示将在奖励传递之前，反之亦然。我会接受训练 在腹侧被盖区多巴胺和GABA神经元的纤维光度记录以及化学发生操纵中， 的mPFC-VTA途径，以测试mPFC是否以特定于化合价的方式调节灵活更新。 无论结果如何，拟议的工作将增加我们对灵活更新 当结果偶然性改变时的行为反应。