PMID- 35435568 OWN - NLM STAT- MEDLINE DCOM- 20220808 LR - 20230802 IS - 1995-8218 (Electronic) IS - 1673-7067 (Print) IS - 1995-8218 (Linking) VI - 38 IP - 8 DP - 2022 Aug TI - Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats. PG - 887-900 LID - 10.1007/s12264-022-00852-7 [doi] AB - Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline. CI - (c) 2022. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences. FAU - Wang, Shi-Da AU - Wang SD AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Wang, Xue AU - Wang X AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Zhao, Yun AU - Zhao Y AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Xue, Bing-Hua AU - Xue BH AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Wang, Xiao-Tian AU - Wang XT AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Chen, Yu-Xin AU - Chen YX AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. FAU - Zhang, Zi-Qian AU - Zhang ZQ AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. AD - 8th People's Hospital of Qingdao, Qingdao, 266041, China. FAU - Tian, Ying-Rui AU - Tian YR AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. AD - School of Public Health, Lanzhou University, Lanzhou, 730000, China. FAU - Xie, Fang AU - Xie F AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. vancoxie@sina.com. FAU - Qian, Ling-Jia AU - Qian LJ AD - Institute of Military Cognitive and Brain Sciences, Academy of Military Medical Sciences, Beijing, 100850, China. newjia@vip.sina.com. LA - eng PT - Journal Article DEP - 20220418 PL - Singapore TA - Neurosci Bull JT - Neuroscience bulletin JID - 101256850 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - *Cognitive Dysfunction/complications MH - DNA Methylation MH - *Homocysteine/adverse effects/metabolism MH - *Hyperhomocysteinemia/metabolism MH - Rats MH - *Stress, Psychological/physiopathology PMC - PMC9352847 OTO - NOTNLM OT - BDNF OT - DNA methylation OT - Homocysteine OT - Stress-associated cognitive decline COIS- The authors listed in this article have no known competing financial interests or personal relationships that may affect the reported work. EDAT- 2022/04/19 06:00 MHDA- 2022/08/09 06:00 PMCR- 2023/08/01 CRDT- 2022/04/18 12:06 PHST- 2021/08/13 00:00 [received] PHST- 2022/01/11 00:00 [accepted] PHST- 2022/04/19 06:00 [pubmed] PHST- 2022/08/09 06:00 [medline] PHST- 2022/04/18 12:06 [entrez] PHST- 2023/08/01 00:00 [pmc-release] AID - 10.1007/s12264-022-00852-7 [pii] AID - 852 [pii] AID - 10.1007/s12264-022-00852-7 [doi] PST - ppublish SO - Neurosci Bull. 2022 Aug;38(8):887-900. doi: 10.1007/s12264-022-00852-7. Epub 2022 Apr 18.