Creating stable memories is critical for survival, as a means to find scarce resources (e.g., food/water) and avoid dangerous situations. However, the dynamic nature of an environment also requires that memories be updated with new information in order to respond to changing reward and threat contingencies. Thus, optimal brain circuits require both stability and flexibility to efficiently create memories and to update them according to ongoing changes in the environment [1]. The vast majority of research on memory processes has focused on forming stable memories that drive behavior, while much less is known about how these memories are updated when new information is provided.

In their recent Neuropsychopharmacology article, Xu et al. [2] identify a specific molecular interaction in the mouse medial prefrontal cortex (mPFC) that helps maintain the persistence of a memory despite new conflicting information. This process occurs during initial learning, is mediated by the ErbB4- NRXN1β interaction in mPFC, and selectively increases excitatory connections onto parvalbumin-positive (PV+) neurons. To block this interaction, the authors developed a novel small peptide, called ErbB4-16P, that directly inhibited ErbB4- NRXN1β interaction while maintaining other ErbB4-mediated actions. By blocking this ErbB4-NRXN1β interaction, the authors blocked the corresponding increase in excitatory connectivity on PV+ interneurons and were able to induce more flexible behavior when mice learned a new reward contingency. Specifically, the authors trained mice to associate odor A with a reward and odor B with no reward. They then performed similar training with two new odors (by rewarding odor C, but not odor D), which the mice quickly learned. When the authors reversed this contingency, and began rewarding odor D, instead of odor C, the control mice took longer to learn this association than during initial learning of odors A and B, showing an interference from the initial training. However, when the authors specifically disrupted the ErbB4-NRXN1β signaling pathway, the mice were able to rapidly learn the new association. Specifically, the improved performance on the reversal task was due to reduced responses to the no-longer-rewarded odor (i.e., correct rejections of incorrect stimuli). Together, these experiments demonstrate that the ErbB4- NRXN1β signaling stabilizes learned information, drives increased excitatory connections onto PV+ interneurons, and contributes to proactive interference to learning new information.

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