The fine arrangement of neuronal connectivity during development involves the coordinated action of guidance cues and their receptors. In adolescence, the dopamine circuitry is still developing, with mesolimbic dopamine axons undergoing target-recognition events in the nucleus accumbens (NAcc), while mesocortical projections continue to grow toward the prefrontal cortex (PFC) until adulthood. This segregation of mesolimbic versus mesocortical dopamine pathways is mediated by the guidance cue receptor DCC, which signals dopamine axons intended to innervate the NAcc to recognize this region as their final target. Whether DCC-dependent mesolimbic dopamine axon targeting in adolescence requires the action of its ligand, Netrin-1, is unknown. Here we combined shRNA strategies, quantitative analysis of pre- and post-synaptic markers of neuronal connectivity, and pharmacological manipulations to address this question. Similar to DCC levels in the ventral tegmental area, Netrin-1 expression in the NAcc is dynamic across postnatal life, transitioning from high to low expression across adolescence. Silencing Netrin-1 in the NAcc in adolescence results in an increase in the expanse of the dopamine input to the PFC in adulthood, with a corresponding increase in the number of presynaptic dopamine sites. This manipulation also results in altered dendritic spine density and morphology of medium spiny neurons in the NAcc in adulthood and in reduced sensitivity to the behavioral activating effects of the stimulant drug of abuse, amphetamine. These cellular and behavioral effects mirror those induced by Dcc haploinsufficiency within dopamine neurons in adolescence. Dopamine targeting in adolescence requires the complementary interaction between DCC receptors in mesolimbic dopamine axons and Netrin-1 in the NAcc. Factors regulating either DCC or Netrin-1 in adolescence can disrupt mesocorticolimbic dopamine development, rendering vulnerability or protection to phenotypes associated with psychiatric disorders.
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.
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...
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