Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter

Abstract

Child abuse (CA) is a major risk factor for depression, and strongly associates with suicidal behavior during adulthood. Neuroimaging studies have reported widespread changes in white matter integrity and brain connectivity in subjects with a history of CA. Although such observations could reflect changes in myelin and oligodendrocyte function, their cellular underpinnings have never been addressed. Using postmortem brain samples from depressed suicides with or without history of CA and matched controls (18 per group), we aimed to characterize the effects of CA on oligodendrocyte-lineage (OL) cells in the ventromedial prefrontal white matter. Using immunoblotting, double-labeling immunofluorescence and stereological estimates of stage-specific markers, we found that CA is associated with increased numbers of mature myelinating oligodendrocytes, accompanied by decreased numbers of more immature OL cells. This was paralleled by an increased expression of transcription factor MASH1, which is involved in the terminal differentiation of the OL, suggesting that CA may trigger an increased maturation, or bias the populations of OL cells toward a more mature phenotype. Some of these effects, which were absent in the brain of depressed suicides with no history of CA, were also found to recover with age, suggesting that changes in the balance of the OL may reflect a transient adaptive mechanism triggered by early-life adversity. In conclusion, our results indicate that CA in depressed suicides is associated with an imbalance of the OL in the ventromedial prefrontal white matter, an effect that could lead to myelin remodeling and long-term connectivity changes within the limbic network.

Early life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms

“…Early life stress in humans has been linked with hypo-myelination in the adult prefrontal cortex (5)(6)(7)(8) , a phenotype also reported in rodent models of ELS (9)(10)(11)(12)20). Present findings provide a possible developmental mechanism for this, by showing that a precocious differentiation of the oligodendrocytic lineage during development could be at the origin of the permanent reduction in the adult OPC pool.…”

“…Importantly, our findings are supported by a transient increase in PLP1 levels as well as by several others, previous observations in other experimental models of sensory deprivation or ELS, showing transient and immediate increase in myelin content, followed by a permanent decrease in adulthood in sensory cortices or cerebellum (36)(37)(38)(39)(40). Moreover, a recent clinical paper indicating that childhood adversity in human biases oligodendrocyte lineage toward a more differentiated phenotype in the ventral mPFC, with more pronounced effects in samples from young individuals that died closer to ELS experience (7).…”

“…The exact developmental mechanisms involved in adult hypomyelination after ELS are still disputed (7,12). Our data favour a precocious differentiation of the oligodendrocyte lineage resulting in a depletion of the OPC pool in adults.…”

“…Current evidence that ELS alters developmental trajectories is essentially based on brain imaging studies in adult patients who experienced childhood adversity. These studies showed altered brain activity and myelin content, notably affecting the medial prefrontal cortex (mPFC), which constitutes a critical hub for emotional control and cognition (5)(6)(7)(8). Since the mPFC has a protracted postnatal development, it is a likely target for environmental challenges occurring in childhood.…”

Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides

“…Recently, oligodendrocyte-lineage (OL) cells have also been associated with depression and suicide. These cells, which allow for a formidable form of brain plasticity by responding to environmental cues and experiences in an activity-dependent manner [13][14][15] , were found to display signs of functional impairments in both post-mortem brain samples from depressed individuals [16][17][18][19][20][21][22][23][24] and stress-induced animal models of depression [25][26][27] . These findings could represent a neurobiological substrate to the altered connectivity and white matter integrity that have been reported in imaging studies [28][29][30][31][32][33][34][35] , highlighting that myelin plasticity in discrete cortico-limbic areas could mediate some of the behavioral changes characterizing depression or modulate individual vulnerability to this mood disorder.…”