Strategy updating mediated by specific retrosplenial-parafascicular-basal ganglia networks

Adaptive behavior requires flexible control over learning and exploitation of potentially viable options. Within a particular task, careful learning of strategies that differ from the initially learned rule is especially important as it sets an individual's strategy repertoire. However, whether and how such strategy updating is mediated by specific brain networks has remained unclear. Retrosplenial cortex (RSC), a cortical area exhibiting extensive connectivity to dorso-medial striatum (DMS) and the hippocampal formation, has been broadly implicated in flexible learning and might be involved in strategy updating. Here, we investigate the specific role of mouse RSC in flexible learning, map relevant RSC-anchored cortico-thalamo-basal ganglia circuits, and dissect their role in strategy updating. Activity in RSC was neither required for initial rule learning nor to switch between previously learned rules but was specifically required to explore and learn new alternative options when previous ones were available but no longer appropriate. Such strategy updating depended on activity in RSC c-Fos+ ensembles associated with the original rule and on their connections to DMS and thalamic parafascicular nucleus (PF) neurons. At the circuit level, rule-related RSC projection neurons branched to innervate both DMS and PF neurons and mediated strategy updating through a RSC-DMS-substantia nigra reticulata (SNr)-PF network, coupling alternative exploration to outcome. In addition, a separate RSC-PF-RSC looped network promoted alternative exploration. Our results uncover cortico-basal ganglia-thalamo and cortico-thalamo networks involving subpopulations of neurons in RSC and PF that specifically control and implement strategy updating.