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.

Social defeat stress: Mechanisms underlying the increase in rewarding effects of drugs of abuse

“…On the other hand, epigenetic mechanisms induced by social stress could be responsible for the changes observed in DA receptors. For instance, rats exposed to maternal separation and social isolation show downregulation of the D1 receptor in the NAc due to hypermethylation of the Drd1a promoter region (Sasagawa et al., ).…”

Effects of early life stress on biochemical indicators of the dopaminergic system: a 3 level meta-analysis of rodent studies

“…Ling et al 2004; Z. Ling et al 2009; Liu et al 2016; Lovic et al 2013; Luchicchi et al 2016; Madruga et al 2006; Matthews et al 2001; Meyer, Nyffeler, Schwendener, et al 2008; Meyer, Nyffeler, Yee, et al 2008; Novak et al 2013; Ognibene et al 2008; Oreland et al 2011; Ozawa et al 2006; Pallarés et al 2013; Panagiotaropoulos et al 2004; Pang et al 2015; Papaioannou et al 2002; Ploj, Roman, and Nylander 2003; Rentesi et al 2013; Reynaert et al 2016; Reznikov and Nosenko 1995; Romano-López et al 2015; Eva Romero et al 2007; E Romero et al 2010; Rossi-George et al 2011; Rots et al 1996; Sasagawa et al 2017; Silvagni et al 2008; Silveira et al 2010; Son et al 2007; Tien et al 2013; Vazquez et al 2007; Vuillermot et al 2012; Wang et al 2009; Weston, Sobolewski, et al 2014; Weston, Weston, et al 2014; Winter et al 2009; Womersley et al 2011; Zager, Mennecier, and Palermo-Neto 2012; Zavitsanou et al 2013; Y. Zhang et al 2015; X.…”

Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress

“…and visceral pain in adulthood following a history of ELS. 15,[23][24][25][26][27] In the current study, we used the odor-associated learning model of neonatal adversity that mimics early attachment to an abusive caregiver. 17 This model takes advantage of the stress-hyporesponsive period, during which the HPA axis of neonates is suppressed.…”