Role of Brain Serotonin in Age-Related Decline in Physical Activity in Mice

Ageing is negatively correlated with physical activity (PA) and this has an undesirable impact on overall health. The neurotransmitter serotonin (5-HT) is known to be inversely correlated with physical activity. Here we investigate a serotonergic neuronal circuit involved in voluntary physical activity during ageing in mice. We injected designed DREADD proteins (Designer Receptors Exclusively Activated by Designer Drugs) that enable non-invasive control of neuronal signalling through the Gq (hMD3q, excitatory) and Gi (hMD4i) G-protein coupled signalling pathways in the dorsal raphe nucleus (DRN) of Tph2 mice (tph2, rate-limiting enzyme in 5HT synthesis) to modulate 5-HT release, or in the ventral segmental area (VTA) of 5-HT2CR Cre mice (5-HT type 2c receptor) to modulate activity in a 5-HT target region. Upon administration of CNO (clozapine-N-Oxide, Designer drug for DREADD) (1mg/kg, IP) and lorcaserin (3mg/kg, IP) we characterised the locomotor activity profile of all mice using TSE Phenomaster. Our results showed that activation of Tph2 cells reduced PA (p < 0.05; Veh, n = 11, 12811 ± 1554 vs CNO, n = 10 8196 ± 2821, t = 2.507,df = 19,) while its inhibition induced locomotion (p < 0.001; Veh, n = 5, 13209 ± 1181, vs CNO, n = 5, 26948 ± 2515, t = 4.944, df = 8. Chemogenetic activation of 5-HT2CR VTA reduced PA (p < 0.05, Veh, n = 6, 6650 ± 1329 vs CNO, n = 9, 3587 ± 401, t = 2.606, df = 13) while its inhibition reverted the effects of lorcaserin (p < 0.01, Lorc + veh n = 6, 10704 ± 1235 vs Lorc + CNO n= 9, 16280 ± 1405, t = 2.930, df = 11) In summary, our data indicate that the serotonin system through the 5-HT2cR signalling in the VTA is involved in the control of locomotion and identify a means to reverse age-related decline in physical activity.