In summary, this study highlighted the effect of HDAC1/miR-124-5p/NPY axis in depression with the major findings suggesting inhibited miR-124-5p or suppressed HDAC1 attenuated learning and memory abilities, increased body weight, suppressed oxidative stress and inflammation, as well as promoted neurotransmitter expression in depressed rats. The gene discussed is NPY; the disease is major depressive disorder.