title: Long-term effects of maternal separation coupled with social isolation on reward seeking and changes in dopamine D1 receptor expression in the nucleus accumbens via DNA methylation in mice.
abstract: Early-life stress has long-lasting effects on the stress response, emotions, and behavior throughout an individual's life. Clinical reports have demonstrated that child abuse victims exhibit impairments in reward-associated behavior; yet, the mechanism for this effect remains unclear. Maternal separation (MS) or MS coupled with social isolation (SI) (MS+SI) is widely used as a model for early-life stress in rodent studies. We employed mice subjected to MS+SI to clarify the long-term effect of early-life stress on reward-seeking involving palatable foods by a conditioned place-preference (CPP) paradigm. Prior MS+SI experience decreased exploration time in a chocolate-paired compartment in adult female mice, but not in male mice. We then focused on the mesolimbic dopamine pathway associated with reward-seeking behavior and measured both mRNA and protein levels of tyrosine hydroxylase (TH) in the ventral tegmental area (VTA) and dopamine D1 and D2 receptors in the nucleus accumbens (NAc). MS+SI female mice had significantly lower D1 receptor mRNA and protein levels than controls, whereas the expression of TH and the D2 receptor was similar in the 2 groups. All mRNA and protein levels were unchanged in MS+SI male mice. When attempting to elucidate the mechanism underlying downregulation of the D1 receptor in the NAc of MS+SI females, we found hypermethylation of the Drd1a promoter region. These results suggest that early-life stress affects reward-seeking behavior in female mice, which may be associated with the downregulation of D1 receptor in the NAc via epigenetic modification of its promoter region.
authors.affiliation: Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Nara, 634-8521, Japan.
authors.forename: Takayo
authors.initials: T
authors.lastname: Sasagawa
authors.affiliation: Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Nara, 634-8521, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Horii-Hayashi
authors.affiliation: Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, 634-8521, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Okuda
authors.affiliation: Department of Anatomy, Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui, 910-1193, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Nara, 634-8521, Japan.
authors.forename: Cho
authors.initials: C
authors.lastname: Azuma
authors.affiliation: Department of Anatomy and Cell Biology, Nara Medical University, Kashihara, Nara, 634-8521, Japan. Electronic address: nmayumi@naramed-u.ac.jp.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishi
mesh_terms: D000818:Animals; D019175:DNA Methylation; D005260:Female; D008297:Male; D008426:Maternal Deprivation; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012737:Sex Factors; D012934:Social Isolation
chemical_list: D017447:Receptors, Dopamine D1
keywords: Conditioned place preference; Dopamine receptor; Early-life stress; Epigenetics; Reward