Sacson, A. | Search bioRxiv

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↗

bioRxiv2019

Dentate gyrus somatostatin cells are required for contextual discrimination during episodic memory encoding

Episodic memory establishes and stores relations among the different elements of an experience, which are often similar and difficult to distinguish. Pattern separation, implemented by the dentate gyrus, is a neural mechanism that allows the discrimination of similar experiences by orthogonalizing synaptic inputs. Granule cells support such disambiguation by sparse rate coding, a process tightly controlled by highly diversified GABAergic neuronal populations, such as somatostatin-expressing cells which directly target the dendritic arbor of granule cells, massively innervated by entorhinal inputs reaching the molecular layer and conveying contextual information. Here, we tested the hypothesis that somatostatin neurons regulate the excitability of the dentate gyrus, thus controlling the efficacy of pattern separation during memory encoding in mice. Indeed, optogenetic suppression of dentate gyrus somatostatin neurons increased spiking activity in putative excitatory neurons and triggered dentate spikes. Moreover, optical inhibition of somatostatin neurons impaired both contextual and spatial discrimination of overlapping episodic-like memories during task acquisition. Importantly, effects were specific for similar environments, suggesting that pattern separation was selectively engaged when overlapping conditions ought to be distinguished. Overall, our results suggest that somatostatin cells regulate excitability in the dentate gyrus and are required for effective pattern separation during episodic memory encoding.\n\nSignificance statementMemory systems must be able to discriminate stored representations of similar experiences in order to efficiently guide future decisions. This is solved by pattern separation, implemented in the dentate gyrus by granule cells to support episodic memory formation. The tonic inhibitory bombardment produced by multiple GABAergic cell populations maintains low activity levels in granule cells, permitting the process of pattern separation. Somatostatin-expressing cells are one of those interneuron populations, selectively targeting the distal dendrites of granule cells, where cortical multimodal information reaches the dentate gyrus. Hence, somatostatin cells constitute an ideal candidate to regulate pattern separation. Here, by using optogenetic stimulation in mice, we demonstrate that somatostatin cells are required for the acquisition of both contextual and spatial overlapping memories.

neuroscience↗