Brain serotonin circuit reverses decline in physical activity with age

Pablo Blanco Martínez de Morentin; Alasdair T. S. Leeson-Payne; Shuwen Mu; Yuliia V. Martynova; Aida Mohammadkhani; Drew M. Neyens; J. Antonio Gonzalez; Jānis Lazovskis; Claudia Cristiano; Daniel R. Crabtree; Claire Fyfe; William Buosi; Daniel Powell; Raffaella Chianese; Matevž Arčon; Guy S. Bewick; Arimantas Lionikas; Graham William Horgan; Ran Levi; Alexandra M. Johnstone; Stephanie L. Borgland; Lora K. Heisler

doi:10.64898/2025.12.27.695444

NeurosciencebioRxivDec 27, 2025

Preprint

Brain serotonin circuit reverses decline in physical activity with age

Pablo Blanco Martínez de Morentin iD, Alasdair T. S. Leeson-Payne iD, Shuwen Mu, Yuliia V. Martynova iD, Aida Mohammadkhani iD, Drew M. Neyens, J. Antonio Gonzalez, Jānis Lazovskis iD, Claudia Cristiano iD, Daniel R. Crabtree iD, Claire Fyfe iD, William Buosi iD, Daniel Powell iD, Raffaella Chianese, Matevž Arčon iD, Guy S. Bewick iD, Arimantas Lionikas iD, Graham William Horgan iD, Ran Levi iD, Alexandra M. Johnstone iD, Stephanie L. Borgland iD, Lora K. Heisler iD

Abstract

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

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