miR-218 in adolescence predicts and mediates vulnerability to stress

Abstract

Adolescence is a period of increased vulnerability to psychiatric disorders including depression.Discovering novel biomarkers to identify individuals who are at high risk is very much needed.Our previous work shows that the microRNA miR-218 mediates susceptibility to stress and depression in adulthood, by targeting the Netrin-1 guidance cue receptor gene Dcc (Deleted in colorectal cancer) in the medial prefrontal cortex (mPFC). Here we investigated whether miR-218 regulates Dcc expression in adolescence and could serve as an early predictor of lifetime stress vulnerability. miR-218 expression in the mPFC increases from early adolescence to adulthood and correlates negatively with Dcc levels. In blood, postnatal miR-218 expression parallels changes occurring in the mPFC. Notably, circulating miR-218 levels in adolescence associate with vulnerability to social defeat stress in adulthood, with high levels associated with social avoidance severity. Indeed, downregulation of miR-218 in the mPFC in adolescence promotes resilience to stress in adulthood, indicating that adolescent miR-218 expression may serve both as a marker of risk and as a target for early interventions. 6 blood. These findings suggest that circulating miR-218 might serve as a sensor of miR-218/DCC changes occurring in the mPFC following adult exposure to chronic stress(31), providing information about effects of environmental risk and protective factors. However, whether circulating levels of miR-218 could serve as an early predictor biomarker of vulnerability to stress needs to be determined.Given the important role of DCC receptors in the adolescent maturation of the mPFC(34, 44), we hypothesize that miR-218 determines Dcc gene expression in the mPFC during this sensitive developmental window and may mediate vulnerability to stress in adulthood. We also propose that circulating levels of miR-218 might serve as a developmental biomarker of depression-like behaviors in adulthood. To address these questions, we assessed whether the levels of miR-218 and Dcc mRNA in the mPFC vary across postnatal development and whether these variations can be detected in blood. We determined whether circulating miR-218 in adolescence predicts individual differences in vulnerability to CSDS in adulthood. METHODS AND MATERIALS AnimalsAll experimental procedures were performed in accordance with the guidelines of the Canadian Council of Animal Care and approved by the McGill University and Douglas Hospital Animal Care Committee. C57BL/6 mice: Adolescent (PND 21 and PND 35) and adult (PD 75±15) male wild-type mice were bred in the animal facilities of the Douglas Hospital. Male pups were weaned at PND 21, group-housed (4 per cage) with same-sex littermates and given access to food and water ad 7 libitum. All mice were kept on a 12-hour light/dark cycle (lights on 08:00), with experimental procedures being performed during the light period.CD-1 mice: Male CD-1 retired breeder mice (>3 months old) obtained from Charles River Canada were used as aggressors in the chronic so...

Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior

“…2B). Despite the number of miRNA sequences present in Map2k7 mRNA, the observed downregulation was moderate, in agreement with the contention that miRNAs fine-tune gene expression [52,53]. Finally, we observed no reduction of Map2k7 in area 25 (Suppl.…”

“…Given the known involvement of serotonin in brain development [76] future studies should determine the relationship of such variants within the developing brain, in particular, the process by which area 32 integrates into prefrontal executive networks. This is highly relevant to our understanding of the onset of psychiatric disorders since the majority begin during adolescence [77,78], a period in which miRNAs changes might significantly contribute to brain vulnerability [52,53]. A) Network analysis using miRNAs deregulated in area 32.…”

MicroRNA regulation of prefrontal cortex development and psychiatric risk in adolescence

“…Nevertheless, changes in microRNA expression in the cortex at any point of the developmental continuum can affect the function of gene networks controlling ongoing homeostatic processes [49]. Emerging results from rodent studies supports the notion that microRNAs are key epigenetic mediators of early environmental programing on neurocircuitry, cognitive development and function throughout the lifespan [33,50,51], even lasting across generations [52,53].…”

“…Dicer, DGCR8) induces dramatic disruption of cortical development, from cell viability and premature progenitor differentiation during corticogenesis to cortical malformations [29,31,32]. MicroRNA control over cortical development extends to adolescence [33], when the prefrontal portion of the cortex continues to undergo substantial maturation [34][35][36][37][38][39][40][41][42], remaining particularly vulnerable to environmental factors.…”

“…Consistent with the adolescent shift in global microRNA expression observed in the PFC in humans [54,55], miR-218 levels in mice increase from early adolescence to adulthood. Postnatal PFC miR-218 and Dcc expression in mice correlate negatively [33]. Disrupting this developmental pattern has enduring behavioral consequences: downregulation of miR-218 in the PFC of adolescent mice via antagomir microinfusion, induces resilience to detrimental effects of chronic social defeat stress in adulthood.…”