Zeidler Zachary, Fernandez Gomez Marta, Gupta Tanya A, Shari Meelan, Wilke Scott A, DeNardo Laura A
Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, Le Conte Ave, Los Angeles, CA 90095, USA.
Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, Le Conte Ave, Los Angeles, CA 90095, USA.
Curr Biol. 2025 Aug 4. doi: 10.1016/j.cub.2025.07.035.
To survive, animals must rapidly learn to avoid predictable threats. Such learning depends on detecting reliable cue-outcome relationships that efficiently drive behavioral adaptations. The medial prefrontal cortex (mPFC) integrates learned information about the environment to guide adaptive behaviors and is critical for threat avoidance. However, most studies focused on well-learned threat avoidance strategies, and the specific inputs that signal avoidability and drive rapid avoidance learning remain poorly understood. Dopamine (DA) inputs from the ventral tegmental area (VTA) potently modulate prefrontal function and are preferentially engaged by aversive stimuli. Pharmacological blockade, DA depletion, and microdialysis experiments implicated DA in threat avoidance but lacked the spatiotemporal resolution required to define the timing of mPFC DA signals during avoidance learning. We used high-resolution tools to dissect the role of the VTA-mPFC DA circuit in rapid avoidance learning. Optogenetic suppression of VTA DA terminals in mPFC selectively slowed learning of a cued avoidance response without affecting cue-shock association learning, reactive escape behaviors, or expression of previously learned avoidance. Using a fluorescent DA sensor, we observed rapid, event-locked DA activity that emerged transiently during learning initiation. Increased DA encoded aversive outcomes and their predictive cues, while decreased DA encoded their omission and predicted how quickly mice learned to avoid. In yoked mice lacking control over shock omission, these dynamics were largely absent. Together, these findings demonstrate that the VTA-mPFC DA circuit is necessary for rapid acquisition of proactive avoidance behaviors and reveal transient event-related DA signals underlying this form of learning.
为了生存，动物必须迅速学会避免可预测的威胁。这种学习依赖于检测可靠的线索-结果关系，这些关系能有效地驱动行为适应。内侧前额叶皮层（mPFC）整合有关环境的学习信息以指导适应性行为，并且对避免威胁至关重要。然而，大多数研究集中在已充分学习的威胁回避策略上，而那些表明可回避性并驱动快速回避学习的特定输入仍知之甚少。来自腹侧被盖区（VTA）的多巴胺（DA）输入有力地调节前额叶功能，并且优先被厌恶刺激激活。药理学阻断、DA耗竭和微透析实验表明DA参与威胁回避，但缺乏在回避学习期间定义mPFC DA信号时间所需的时空分辨率。我们使用高分辨率工具来剖析VTA-mPFC DA回路在快速回避学习中的作用。对mPFC中VTA DA终末的光遗传学抑制选择性地减缓了线索回避反应的学习，而不影响线索-电击关联学习、反应性逃避行为或先前学习的回避行为的表达。使用荧光DA传感器，我们观察到在学习开始时短暂出现的快速、事件锁定的DA活动。DA增加编码厌恶结果及其预测线索，而DA减少编码它们的缺失，并预测小鼠学会回避的速度。在对电击缺失缺乏控制的配对小鼠中，这些动态变化基本不存在。总之，这些发现表明VTA-mPFC DA回路对于快速获得主动回避行为是必要的，并揭示了这种学习形式背后与事件相关的短暂DA信号。
