Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience

• Published in: Cell reports (Cambridge) Vol. 42; no. 3; p. 112149
• Main Authors: Nagai, Yuma, Kisaka, Yuri, Nomura, Kento, Nishitani, Naoya, Andoh, Chihiro, Koda, Masashi, Kawai, Hiroyuki, Seiriki, Kaoru, Nagayasu, Kazuki, Kasai, Atsushi, Shirakawa, Hisashi, Nakazawa, Takanobu, Hashimoto, Hitoshi, Kaneko, Shuji
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2023; Elsevier
• Subjects: Dentate Gyrus; Depressive Disorder, Major; Dorsal Raphe Nucleus; Humans; neuronal ensembles; Serotonergic Neurons; serotonin; Serotonin - pharmacology; stress; neuronal ensembles; stress; serotonin; dentate gyrus
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112149

Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects. [Display omitted] •Activation of dorsal raphe serotonin neurons produces an antidepressant-like effect•Activation of dDG-positive memory ensembles produces an antidepressant-like effect•Dorsal raphe serotonin neurons preferentially activate dDG-positive memory ensembles•Dopamine mediates the positive ensemble reactivation and active coping behaviors Serotonergic neurons are central to major depressive disorder pathophysiology and treatment. Repeatedly recalling positive episodes is effective for major depressive disorder. Nagai et al. show that dorsal raphe serotonergic neurons preferentially activate positive-experience-associated neuronal ensembles in the dorsal dentate gyrus, a key brain region in memory processing.