The ability to rapidly adapt to novel situations is essential for survival, and this flexibility is impaired in many neuropsychiatric disorders¹. Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Exposure to novelty recruits the hippocampus and medial prefrontal cortex (mPFC)² and may prime hippocampal–prefrontal circuitry for subsequent learning-associated plasticity. Here we show that novelty resets the neural circuits that link the ventral hippocampus (vHPC) and the mPFC, facilitating the ability to overcome an established strategy. Exposing mice to novelty disrupted a previously encoded strategy by reorganizing vHPC activity to local theta (4–12 Hz) oscillations and weakening existing vHPC–mPFC connectivity. As mice subsequently adapted to a new task, vHPC neurons developed new task-associated activity, vHPC–mPFC connectivity was strengthened, and mPFC neurons updated to encode the new rules. Without novelty, however, mice adhered to their established strategy. Blocking dopamine D1 receptors (D1Rs) or inhibiting novelty-tagged cells that express D1Rs in the vHPC prevented these behavioural and physiological effects of novelty. Furthermore, activation of D1Rs mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC–mPFC circuitry, thereby enabling subsequent learning-associated circuit plasticity.

快速适应新情况的能力对于生存至关重要，而这种灵活性在许多神经精神疾病中都会受损¹。因此，了解新颖性是否以及如何准备或启动大脑回路以促进认知灵活性具有重要的转化相关性。接触新奇事物会招募海马体和内侧前额叶皮层 (mPFC) ²并可能为随后的学习相关可塑性启动海马体-前额叶回路。在这里，我们表明新颖性重置了连接腹侧海马体 (vHPC) 和 mPFC 的神经回路，促进了克服既定策略的能力。通过将 vHPC 活动重组为局部 theta (4-12 Hz) 振荡并削弱现有 vHPC-mPFC 连接，将小鼠暴露于新奇事物会破坏先前编码的策略。随着小鼠随后适应新任务，vHPC 神经元开发出新的任务相关活动，vHPC-mPFC 连接得到加强，并且 mPFC 神经元更新以编码新规则。然而，如果没有新奇，老鼠就会坚持它们既定的策略。阻断多巴胺 D1 受体 (D1Rs) 或抑制在 vHPC 中表达 D1Rs 的新奇标记细胞可防止这些新奇的行为和生理效应。此外，D1Rs 的激活模仿了新奇的效果。这些结果表明，新颖性通过 D1R 介导的 vHPC-mPFC 电路重置促进适应性学习，从而实现后续学习相关的电路可塑性。