Epidemiological studies revealed deficits in cognitive learning and memory in smokers who withdrawal from smoking, but the molecular mechanisms underlying it is unclear. Here, we employed the novel object recognition task (NORT) to evaluate cognitive memory and found impaired memory and motor skills after withdrawal from chronic
nicotine. Myelin sheath hastens the conduction of signals along axons and thus plays a critical role in learning and memory. We found no effect of
nicotine withdrawal on the myelination in both of the Ventral tegmental area (VTA) and Nucleus accumbens (NAc) regions, but unexpectedly, we observed a
demyelination phenomenon in the medial prefrontal cortex (mPFC) after withdrawal from chronic
nicotine. Moreover, we found a positive correlation between the impaired memory and
demyelination, and
pharmaceutical rescue of myelination by
clemastine specifically improved the impaired recognition memory but not the decreased motor skills caused by withdrawal from chronic
nicotine. We further found
nicotine directly acts on oligodendrocytes with OPCs potential to decrease their myelination process. Taken together, these results demonstrate
demyelination in the mPFC causes impaired recognition memory and reveal a potential of enhancing myelination as a therapeutic strategy to alleviate cognitive
memory deficits caused by smoking withdrawal.