Adverse maternal environment and western diet impairs cognitive function and alters hippocampal glucocorticoid receptor promoter methylation in male mice

Abstract

Adverse maternal environment (AME) and high-fat diet in early childhood increase the risk of cognitive impairment and depression later in life. Cognitive impairment associates with hippocampal dysfunction. A key regulator of hippocampal function is the glucocorticoid receptor. Increased hippocampal GR expression associates with cognitive impairment and depression. Transcriptional control of GR relies in part upon the DNA methylation status at multiple alternative initiation sites that are tissue specific, with exon 1.7 being hippocampal specific. Increased exon 1.7 expression associates with upregulated hippocampal GR expression in early life stress animal models. However, the effects of AME combined with postweaning western diet (WD) on offspring behaviors and the expression of GR exon 1 variants in the hippocampus are unknown. We hypothesized that AME and postweaning WD would impair cognitive function and cause depression-like behavior in offspring in conjunction with dysregulated hippocampal expression of total GR and exon 1.7 variant in mice. We found that AME-WD impaired learning and memory in male adult offspring concurrently with increased hippocampal expression of total GR and GR 1.7. We also found that increased GR 1.7 expression was associated with decreased DNA methylation at the GR 1.7 promoter. We speculate that decreased DNA methylation at the GR 1.7 promoter plays a role in AME-WD induced increase of GR in the hippocampus. This increased GR expression may subsequently contribute to hippocampus dysfunction and lead to the cognitive impairment seen in this model. K E Y W O R D Sadverse maternal environment, DNA methylation, GR, hippocampus, western diet the Clinical and Translational Research Core Lab in the

Adverse Maternal Environment Alters MicroRNA-10b-5p Expression and Its Epigenetic Profile Concurrently with Impaired Hippocampal Neurogenesis in Male Mouse Hippocampus

“…All experiments were conducted according to the Public Health Services Policy on Human Care and Use of Laboratory Animals and all procedures were approved by the Medical College of Wisconsin Institutional Animal Care and Use Committee [40]. The mouse model of AME used in this study has been previously described [41]. Briefly, AME was induced in mice by exposing sixweek-old C57/Bl6 female mice randomly to either a control diet (10% fat without cholesterol and sucrose, Research Diet Inc., New Brunswick, NJ, USA, Product# D14020502) or a WD (40% fat, composed of increased saturated fat, cholesterol, and sucrose, Research Diet Inc., Product# D12079B) for 5 weeks prior to pregnancy and throughout lactation.…”

“…Like a protein-coding gene, miR expression can be epigenetically regulated [31][32][33]. Additionally, measurable epigenetic changes often occur in effected genes following an adverse early life environment [41]. We then determined the effect of AME on DNA methylation status and histone code at miR-10b promoter.…”

“…together with postweaning WD impairs learning and memory function in adult male mice [7]. Unfortunately, how early life insults affect cognition functions later in life remain poorly understood.…”

Western Diet: Implications for Brain Function and Behavior

“…Human studies have examined how WD impairs hippocampal function and ingestive behavior (Stevenson et al, 2020). Several animal studies have been performed using memory tasks showing that WD consumption impairs hippocampal-dependent memory tasks (Francis and Stevenson, 2013;Ke et al, 2020). For example, a recent meta-analysis included 41 studies in which different tasks to assess hippocampal-dependent spatial learning and memory were carried out, and they showed that high-fat and -sugar diets may impair hippocampal-dependent forms of cognition (Abbott et al, 2019).…”

Is Early Life Adversity a Trigger towards Inflammageing?

“…Epigenetic changes are most visible in the glucocorticoid receptor (GR) gene promoter and subsequent GR signalling in the central tissues of the GC feedback loop (Koss and Gunnar, 2018). Differential methylation of the GR has been associated with adverse maternal environment (Stonawski et al, 2019), diet (Ke et al, 2020), early life stress (Holmes, 2019), exposure to environmental toxins (Meakin et al, 2019), chronic stress (Rowson et al, 2019) and institutionalisation (Elwenspoek et al, 2019) among other sources. Epigenetic modification of the GR and related genes presents the best biomarker of ELA up to date, but these methylation changes might only occur in brain regions, making them inaccessible for preventive medicine (Lewis et al, 2020), since the peripheral GR does not appear to be functionally or transcriptionally altered (Elwenspoek et al, 2019).…”