The VGLUT3 positive neurons of the median raphe region promote long-term spatial memory through time-dependent mechanisms

Fazekas, Csilla Lea and Szocsics-Török, Bibiána and Szabó, Adrienn and Correia, Pedro and Chaves, Tiago and Fabre, Véronique and Daumas, Stéphanie and Zelena, Dóra (2026) The VGLUT3 positive neurons of the median raphe region promote long-term spatial memory through time-dependent mechanisms. PROGRESS IN NEUROBIOLOGY, 260. No. 102904. ISSN 0301-0082

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Abstract

Episodic memory and related forms of learning depend critically on the hippocampus, whose activity is regulated by brainstem inputs that remain incompletely understood. The midbrain median raphe region (MRR) is a key regulator of forebrain circuits and, while classically recognised as serotonergic, many of its neurons also release glutamate. Notably, a subset of MRR neurons projecting to the hippocampus expresses the vesicular glutamate transporter type 3 (VGLUT3), suggesting a glutamatergic contribution. Moreover, electrophysiological data indicate that these MRR-VGLUT3 + neurons influence hippocampal oscillations and therefore, hippocampusdependent learning and memory. Our goal was to investigate the role of MRR-VGLUT3 + neurons in hippocampus-dependent learning and memory. Using VGLUT3-Cre mice of both sexes, we employed adenoassociated viral vectors to selectively activate MRR-VGLUT3 + neurons during the water maze task, a known hippocampus-dependent behavioural paradigm. Neuronal excitation was achieved by chemogenetics (DREADDs) or, to probe temporally restricted effects, by optogenetics (Channelrhodopsin2) during the spatial reference memory phase. Given the involvement of MRR and VGLUT3 + neurons in locomotion and anxiety-like behaviours, open field and elevated plus maze assays were also performed but yield inconclusive results. We found that chronic chemogenetic excitation did not alter learning but enhanced long-term memory performance, a finding replicated in an independent cohort. In contrast, acute optogenetic excitation had no effect, suggesting that MRRVGLUT3 + neurons may contribute to memory related processes in a temporally specific manner.

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