Depression in adolescents. Brain structure and myelination, translational markers. – ADODEP

Adolescence is a key developmental period for those neurobiological processes that underly emotional and cognitive functions in adulthood. The pathophysiology of mood disorders has recently been associated with maturation changes in networks implicated in emotional regulation. Clinically diagnosed depression can begin as early as at age 13, often associated with or preceded by anxiety disorders. It is often underdiagnosed, which carries the risk of outcome in resistant depressions in adulthood. Little is known on the early brain structure changes associated with depression that appear during this brain maturation period. We hypothesize that changes in frontal-limbic connectivity related to myelination abnormalities could underlie vulnerability for depression.
The aims of the present proposal are (1) to identify the changes in brain morphometry and white matter microstructure in emotional networks associated with depression traits both in adolescent humans and in peripubertal mouse models of depression; (2) to analyse myelin structural changes, in peripubertal mouse models of depression; (3) to examine myelin genes and signaling pathways implicated in myelination in these mice; (4) to investigate the effects of antidepressant treatment with fluoxetine on brain structure in mice; and (5) to assess the changes in brain structure in adolescents at follow-up a year later.
The above aims will be achieved through studies in humans combined with translational approaches in mice.
In the clinical study, 40 adolescents with a Major Depressive Episode will be examined using structural T1 magnetic-resonance imaging and diffusion tensor imaging (DTI). They will be compared with 40 healthy controls matched for age and gender. Grey and white matter changes will be assessed. Additionally, the same neuroimaging biomarkers will be investigated in 80 subthreshold depressed adolescents extracted from the IMAGEN database (N=2000) assembled through a FP6-funded multi-site consortium in Europe, to explore white matter development before full-blown depression appears. Those “at-risk” subjects will be compared with 100 matched healthy controls from the database.
In the translational approach, we will employ established mouse depression models with focus on the peripubertal period to study myelination in adolescence, and to identify imaging and molecular biomarkers associated with depressive-like behavior. After completion of behavioral protocols, ex vivo DTI studies will be performed, followed in the same samples by detailed histological and molecular analysis of myelin structure, in the regions of interest. Myelin genes, the myelination process and signaling pathways will also be investigated.
In follow-up studies, the effects of fluoxetine on peripubertal depressive behavior and on white matter microstructure and myelin structure will be prospectively assessed in mice. In adolescents, the effects of naturalistic therapeutic interventions on brain structure will be assessed by comparing the neuroimaging measures at inclusion with those from a year later.
Finally, human and mice data will be compared using multivariate statistics. Covariation patterns between DTI and behavioral/clinical variables will be assessed in each species, and will be subsequently compared between species in analogous regions.
The findings should lead to the identification of early biomarkers of depression, generate new knowledge on interactions between early depression signs and myelination abnormalities in the developing brain, and provide insight on the effects of early antidepressant treatments on white matter tracts maturation in adolescence. Such findings carry a far ranging potential impact on early intervention and preventive therapeutic strategies.