Peripheral ERK modulates acupuncture-induced brain neural activity and its functional connectivity.

Acupuncture has been widely used as a therapeutic intervention, and the brain network plays a crucial role in its neural mechanism. This study aimed to investigate the acupuncture mechanism from peripheral to central by identifying how the peripheral molecular signals induced by acupuncture affect the brain neural responses and its functional connectivity. We confirmed that peripheral ERK activation by acupuncture plays a role in initiating acupuncture-induced peripheral proteomic changes in mice. The brain neural activities in the neocortex, hippocampus, thalamus, hypothalamus, periaqueductal grey, and nucleus of the solitary tract (Sol) were significantly changed after acupuncture, and these were altered by peripheral MEK/MAPK inhibition. The arcuate nucleus and lateral hypothalamus were the most affected by acupuncture and peripheral MEK/MAPK inhibition. The hypothalamic area was the most contributing brain region in contrast task PLS analysis. Acupuncture provoked extensive changes in brain functional connectivity, and the posterior hypothalamus showed the highest betweenness centrality after acupuncture. After brain hub identification, the Sol and cingulate cortex were selected as hub regions that reflect both degree and betweenness centrality after acupuncture. These results suggest that acupuncture activates brain functional connectivity and that peripheral ERK induced by acupuncture plays a role in initiating brain neural activation and its functional connectivity.