Regular versus Irregular Exercise Differentially Modulates Hippocampal‐Hepatic Acetylcholine Flux to Coordinate Fear Memory Extinction and Liver Inflammation

Despite the known benefits of exercise, an in-depth comparison of the effects of regular versus irregular exercise on brain-body interactions and molecular mechanisms remains lacking. This study demonstrates that regular exercise robustly enhances fear memory extinction in mice, whereas irregular exercise has only mild effects. This divergence arises from regular rather than irregular exercise strongly inhibiting axonal mRNA transport and local translation of choline acetyltransferase (ChAT) in septal cholinergic neurons projecting to the hippocampus, thereby reducing hippocampal acetylcholine (ACh) levels and inhibiting α7 nicotinic acetylcholine receptor (α7-nAChR) activation on astrocytes. Critically, this hippocampal ACh-α7-nAChR signaling modulates hepatic ACh via the amygdala-dorsal motor nucleus of the vagus (DMV)-hepatic vagus circuit. Irregular exercise inhibits this pathway inadequately, so that increasing hepatic ACh flux and recruiting a novel neutrophil subset characterized by high expression of F-box and leucine-rich repeat protein 6 (FBXL6^high). Subsequent abnormal iron transport from these neutrophils to hepatocytes promotes the metabolism of arachidonic acid into the proinflammatory mediators prostaglandin H2 (PGH2) and leukotriene B4 (LTB4), exacerbating nonalcoholic fatty liver disease. The findings elucidate the essential mechanisms underlying the neurometabolic benefits of regular exercise and the pathological risks of irregular exercise, offering transformative insights for preventive strategies.