Zanoni, M. B. | bioRxiv Science

bioRxiv2025

Cortical Serotonin Type 2A Receptor Activation Shields Episodic-like Memories from Retroactive Interference in Rodents

The acquisition of temporally proximate information can impair the brains ability to consolidate earlier experiences, resulting in retroactive interference (RI). Recognition-based behavioral paradigms are well-suited for investigating RI in rodents, particularly those involving sequential learning episodes. The medial prefrontal cortex (mPFC) integrates multimodal information relevant to the regulation of memory interference and is strongly modulated by the serotonergic system. Serotonin 2A receptors (5-HT2AR), which are densely expressed in the mPFC, have been shown to influence the retrieval of competing object-recognition memories. However, their role in other phases of memory processing, particularly in modulating RI, remains unclear. Using a modified version of the object recognition task designed to induce RI, combined with pharmacological manipulation of 5-HT2AR, we demonstrate that RI specifically impairs the object-related component of memory. Moreover, serotonin signaling through 5-HT2AR is necessary to prevent RI. Strikingly, activating 5-HT2AR before retrieval can rescue the expression of memories affected by RI, suggesting that RI may not erase memory traces but rather hinder their access.

neuroscience↗

bioRxiv2025

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

Forgetting is a ubiquitous phenomenon actively promoted in many species. The act of remembering some experiences can cause forgetting of others in both humans and rats. We previously found that when rats retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting (RIF) relies on prefrontal control processes, is competition-dependent, and 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 active forgetting remains unexplored. Here, we had rats perform a task known to induce RIF and pharmacologically manipulated the activity and signaling of serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2C in the medial prefrontal cortex (mPFC), as well as to inhibit downstream effectors. Our findings reveal a specific role for prefrontal serotonin signaling in RIF. Whereas 5-HT2C receptor manipulation had no effect, activating 5-HT1A or blocking 5-HT2A receptors in the mPFC abolished RIF. By contrast, activating 5-HT2A receptors promoted RIF under conditions in which it is normally reduced. Further analyses identified the PI3K/AKT pathway as a downstream effector of 5-HT2A receptor signaling, suggesting a specific molecular mechanism through which serotonin modulates inhibitory control over memory. These results uncover a previously unrecognized serotonergic modulation of adaptive forgetting, identifying specific receptor subtypes that link prefrontal serotonin signaling to inhibitory control over memory competition.

animal behavior and cognition↗