Serotonin signaling in the rat prefrontal cortex is required for Retrieval-Induced Forgetting

Forgetting is a ubiquitous phenomenon that is actively promoted in many species. The act of remembering some experiences can cause the forgetting of others in both humans and rats. We previously found that when rats need to retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, retrieval-induced forgetting (RIF) relies on prefrontal control processes, is competition-dependent, and is cue-independent. RIF is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where memories are stored. Serotonin plays a crucial role in behaviors requiring high cognitive demand, including memory processes, partly through its modulation of Prefrontal Cortex activity. However, its potential involvement in regulating forgetting remains unexplored. Here, we exposed rats to the RIF tssk and employed a pharmacological approach to manipulate the activity and signaling of serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2C in the medial prefrontal cortex (mPFC) of rats, as well as to inhibit downstream effectors. Our findings reveal a distinct role for prefrontal serotonin signaling in RIF. While 5-HT2C receptor manipulation had no effect, blocking 5-H21A or 5-HT2A receptors in the mPFC abolished RIF, demonstrating their necessity in this process. Strikingly, further analysis identified the PI3K/AKT pathway as a key downstream effector of 5-HT2A receptor activation, suggesting a specific molecular mechanism through which serotonin modulates inhibitory control over memory. These results uncover a previously unrecognized serotonergic modulation of adaptive forgetting, linking prefrontal serotonin signaling to the regulation of memory competition.