title: Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.
abstract: Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea.
authors.forename: Mi Kyoung
authors.initials: MK
authors.lastname: Seo
authors.affiliation: Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea.
authors.forename: Nguyen Ngoc
authors.initials: NN
authors.lastname: Ly
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea.
authors.forename: Chan Hong
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea.
authors.forename: Hye Yeon
authors.initials: HY
authors.lastname: Cho
authors.affiliation: Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea.
authors.forename: Cheol Min
authors.initials: CM
authors.lastname: Choi
authors.affiliation: Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea.
authors.forename: Le Hoa
authors.initials: LH
authors.lastname: Nhu
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea; Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea; Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea.
authors.forename: Jung Goo
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea.
authors.forename: Bong Ju
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea.
authors.forename: Gyung-Mee
authors.initials: GM
authors.lastname: Kim
authors.affiliation: College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
authors.forename: Bong June
authors.initials: BJ
authors.lastname: Yoon
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea; Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea. Electronic address: swpark@inje.ac.kr.
authors.forename: Sung Woo
authors.initials: SW
authors.lastname: Park
authors.affiliation: Paik Institute for Clinical Research, Republic of Korea; Department of Health Science and Technology, Graduate School of Inje University, Republic of Korea; Department of Psychiatry, School of Medicine, Haeundae Paik Hospital, Inje University, Busan, Republic of Korea. Electronic address: neuro109@hanmail.net.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001010:Anxiety, Separation; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D015283:Citalopram / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D011247:Pregnancy; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000523:psychology*; D013550:Swimming / Q000523:psychology
chemical_list: D018687:Antidepressive Agents, Second-Generation; D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D015283:Citalopram; C498619:Hdac5 protein, rat; D006655:Histone Deacetylases
keywords: BDNF; Epigenetic mechanism; Escitalopram; Maternal separation; Restraint stress