Species-conserved mechanisms of abstract rule learning promote cognitive flexibility in complex environments

Rapid learning in complex and changing environments is a hallmark of intelligent behavior. Humans achieve this in part through abstract concepts applicable to multiple, related situations. It is unclear, however, whether some of the underlying computational mechanisms also exist in other species. We combined behavioral, computational and electrophysiological analyses of a multidimensional rule-learning paradigm in rats and humans. We report that both species infer task rules by sequentially testing different hypotheses, rather than learning the correct action for all possible combinations of task-related cues. Neural substrates of hypothetical rules were detected in prefrontal network activity of both species. This species-conserved mechanism reduces task dimensionality and explains key experimental observations: sudden behavioral transitions and facilitated learning after prior experience. Our findings open the black box of hypothesis testing in rodents and provide a foundation for the translational investigation of impaired cognitive flexibility. ### Competing Interest Statement AML has received consultant fees from the American Association for the Advancement of Science, Atheneum Partners, Blueprint Partnership, Boehringer Ingelheim, Daimler und Benz Stiftung, Elsevier, F. Hoffmann-La Roche, ICARE Schizophrenia, K. G. Jebsen Foundation, L.E.K Consulting, Lundbeck International Foundation (LINF), R. Adamczak, Roche Pharma, Science Foundation, Sumitomo Dainippon Pharma, Synapsis Foundation Alzheimer Research Switzerland, System Analytics, and has received lectures fees including travel fees from Boehringer Ingelheim, Fama Public Relations, Institut d'investigacions Biomediques August Pi i Sunyer (IDIBAPS), Janssen-Cilag, Klinikum Christophsbad, Goeppingen, Lilly Deutschland, Luzerner Psychiatrie, LVR Klinikum Duesseldorf, LWL Psychiatrie Verbund Westfalen-Lippe, Otsuka Pharmaceuticals, Reunions i Ciencia S. L., Spanish Society of Psychiatry, Suedwestrundfunk Fernsehen, Stern TV, and Vitos Klinikum Kurhessen. All other authors declare that they have no competing interests.