Novelty selectively permits learning-associated plasticity in ventral tegmental-hippocampal-prefrontal circuitry

The ability to modify established behavior in novel situations is essential. We designed a behavioral paradigm to test whether novelty exposure facilitates behavioral flexibility. Male mice ran free choice sessions in which they can freely choose an arm of a T-maze to get a reward for 3 days. As a result, mice developed an efficient strategy to simply choose one particular side 90 % of the time (arm bias). The following day, mice were exposed to either a novel or familiar arena and trained on a delayed-non-match-to-sample flexible choice task. Mice had to learn to overcome their established bias and flexibly choose an arm opposite to the sample arm. We previously reported that novelty facilitates this flexible learning by weakening existing connectivity in the ventral hippocampal-medial prefrontal (vHPC-mPFC) circuit. This allows learning-induced connectivity re-strengthening during subsequent flexible choice training in a dopamine D1-receptor (D1R)-dependent mechanism (Park et al. Nature 2021). The present study examined local field potential (LFP) coherence in the HPC, mPFC, and ventral tegmental area (VTA) circuit. As mice exposed to novelty learned to overcome previously established spatial bias, the vHPC strengthens its coherence with the VTA and mPFC in theta frequency (4–8 Hz). Novelty or learning did not affect circuits involving the dorsal HPC. Pharmacologically blocking D1Rs in the vHPC abolished the behavioral and physiological impacts of novelty. Thus, novelty promotes behavioral adaptation by permitting learning-associated plasticity in the vHPC-mPFC and VTA-vHPC circuit, a process mediated by D1Rs in the vHPC.