Effect of ninjin'yoeito on age-related decline in responsiveness of the brain reward system in mice

The reward system involved in the regulation of appetite and motivated behaviors involves mesolimbic dopamine signaling from the ventral tegmental area (VTA) to the nucleus accumbens (Nac). Age-related loss of dopaminergic neurons and weakening of dopamine signals reportedly cause reward system dysfunction, and similarly, age-related changes in microglia in the VTA have been suggested to be involved in this dysfunction. Ninjin'yoeito (NYT), a traditional Japanese herbal medicine, has been reported to improve anorexia, apathy, and the decline in motivation-related behavior in frail Alzheimer's disease patients and older animal models. Although behavioral and electrophysiological analyses suggest that NYT may affect dopamine signaling, the effects of NYT on the reward system remain unclear. The present study aimed to determine whether NYT modulates dopamine-mediated reward circuits in older mice, and whether its effects are linked to microglial modulation in the VTA. Repeated NYT administration restored the responsiveness of dopaminergic neurons in the VTA and increased dopamine release in the Nac, causing an increase in grooming behavior with sucrose stimulation in older mice. Although NYT did not affect cellular senescence of dopaminergic neurons or glial cells, including astrocytes and microglia, it reduced phosphorylation of TANK-binding kinase 1 and expressions of NLRP3 and IL-1β in the VTA. Furthermore, NLRP3 expression in VTA microglia, but not astrocyte, was attenuated by NYT. Our results suggest that NYT may suppress age-related inflammation in the VTA, thereby ameliorating age-related hypovolition.