Reset of hippocampal-prefrontal circuitry facilitates learning

Flexibly adapting to novel situations is critical for survival, which is impaired in neuropsychiatric disorders(1). Thus, understanding whether and how novelty prepares, or primes, brain circuitry to facilitate cognitive flexibility has important translational relevance. Novelty recruits the hippocampus and medial prefrontal cortex (mPFC)(2) and may prime hippocampal-prefrontal circuitry for subsequent learning-associated plasticity. We find that novelty resets ventral hippocampal-prefrontal (vHPC-mPFC) circuitry and facilitates overcoming 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 encoding with new rules. Without novelty, mice adhered to their established strategy. Blocking dopamine D1-receptors (D1Rs) or inhibiting novelty-tagged cells expressing D1Rs in the vHPC prevented these behavioral and physiological effects of novelty. Further, D1R activation mimicked the effects of novelty. These results suggest that novelty promotes adaptive learning by D1R-mediated resetting of vHPC-mPFC circuitry, thereby enabling learning-associated circuit plasticity.