Vascular dementia (VD), the most common of cognitive disorders after Alzheimer's disease (AD), is a serious problem worldwide (Jia et al., 2020). The causes of VD is complicated (Duncombe et al., 2017; Rundek et al., 2022). Chronic cerebral hypoperfusion (CCH) is a major cause of VD. But there remains a lack of effective treatment for VD after stroke, because the mechanisms underlying chronic ischemia are not fully clear. Ferroptosis (Yan et al., 2021), autophagy (Che et al., 2017), and oxidative stress (Chrishtop et al., 2020) and inflammation (Siracusa et al., 2017; Yao et al., 2023) have been implicated in this process. Synaptic plasticity is fundamental for normal cognition, and its impairment underlies many signaling pathway changes that contribute to cognitive dysfunction (Thangwong et al., 2022). Our previous studies have shown that CCH also affects synaptic proteins via miRNA 134 and miRNA 201 (Liu et al., 2019; Ren et al., 2018). Hence, novel targets for VD are needed.

RNA modifications, refers to the study of post-transcriptional modifications of RNA molecules, have emerged as a novel layer of transcriptomic regulation. RNA modifications have been characterized not only in non-coding RNA, but also in messenger RNA (mRNA) (Boccaletto et al., 2018). The post-transcriptional modifications of mRNA, which include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytidine (m5C), N7-methylguanosine (m7G), and N6,2-O-dimethyladenosine (m6A) is a new layer to regulating mRNA metabolism and gene expression. Among them, Methylation at the N6 position of adenosine is referred to as m6A, m6A is one of the most abundant modifications of the mRNA (Dominissini et al., 2012). m6A is highly enriched in the brain, the transcripts in the brain harboring this modification (Chang et al., 2017). m6A profiles in the human brain show functional enrichment in synaptic and neuronal pathways for genes harboring brain-specific m6A (Xiong et al., 2021). Notably, m6A participates in critical neurobiological functions, including synaptic plasticity and learning and memory (Livneh et al., 2020; Widagdo and Anggono, 2018). Recent studies have shown that m6A in the molecular mechanisms closely associated with synaptic connectivity and psychiatric disorders, m6A profiles altered in neurodegenerative and psychiatric disorders, including Alzheimer's disease (Han et al., 2020; Shafik et al., 2021), Parkinson's disease (Geng et al., 2023), Huntington's disease (Pupak et al., 2022), alcohol use disorder (Liu and Zhang, 2022), and post-traumatic stress disorder (PTSD) (Reis et al., 2022). Consequently, this may have important implications for understanding the molecular mechanisms of VD.

Fat mass and obesity-associated gene (FTO) is the first obesity-susceptibility gene to be identified via a genome-wide association study in 2007 (Frayling et al., 2007) . Further studies revealed that FTO is a well-characterized RNA demethylase and is highly expressed in multiple brain regions (Gerken et al., 2007). Previous studies demonstrated that FTO in the brain could regulate postnatal growth of mice (Gao et al., 2010), dopaminergic circuitry within the midbrain (Hess et al., 2013), memory processes in the prefrontal cortex (Widagdo et al., 2016) and the hippocampus (Engel et al., 2018; Li et al., 2017; Spychala and Rüther, 2019; Walters et al., 2017), brain development (Li et al., 2017), adult neurogenesis (Li et al., 2017), and axonal regeneration (Weng et al., 2018). Some evidence revealed that FTO was associated with depressive symptoms (Milaneschi et al., 2014) and involved in the pathogenesis of depression (Sun et al., 2019). However, whether FTO contributes to cognitive impairment after CCH remains to be determined.

In the present study, we used rats after 4 weeks of cerebral ischemia, which are formed by two-vessel occlusion (2VO) to mimic the early stage of VD pathological process, to further explore the functions of FTO in synaptic loss that are involved in cognitive impairment.