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; 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.

项目摘要/摘要 为了有效地穿越环境，必须学会区分预测的线索 不同方式的结果，例如欲望的奖励或厌恶性冲击。在动态环境中 提示预测有意义或厌恶结果的提示会出乎意料地改变，它可以灵活地更新 行为响应，同时保留回忆以前的关联的能力。损害的能力 根据结果​​适当应对线索是许多精神疾病的证据。这 我的博士后培训的总体目的是更好地了解负责更新的神经电路 以前学到的提示结果协会。 大型文献在开胃菜的初步学习中实施了腹侧盖区域（VTA） 厌恶的关联。 VTA中的多巴胺和γ-氨基丁酸（GABA）神经元都涉及 在食欲和厌恶学习的不同方面单独或合作。初次学习后，我 假设媒体调节了对结果突发事件的变化的灵活响应 前额叶皮层（MPFC）以价为特定的方式向VTA投射。在行为上量化初始 学习以及更新提示结果协会，我将在中使用灵活的应急学习（FCL）任务 三个不同的提示与食欲（糖颗粒奖励）配对，一种厌恶 结局（轻度脚冲击）或没有结果。学习后，食欲和厌恶的结果扭转了这种情况 以前的提示将与震惊配对，而将在奖励交付之前，反之亦然。我将受到训练 在VTA多巴胺和GABA神经元的纤维光度计记录中以及化学发生操作 MPFC-VTA途径测试MPFC是否以价为特定方式调节灵活更新。 无论结果如何，拟议的工作都将增加我们对灵活更新的理解 当结果突发事件发生变化时，行为响应。