Dataset Information

Sex-specific impact of prenatal androgens on social brain default mode subsystems.

ABSTRACT: Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has no effect in females. Since testosterone can work directly via the androgen receptor (AR) or indirectly via the estrogen receptor through aromatase conversion to estradiol, we further examined how a potent non-aromatizable androgen, dihydrotestosterone (DHT), acts via the AR to influence gene expression in human neural stem cells (hNSC)-particularly for genes of high-relevance for DMN circuitry. DHT dysregulates a number of genes enriched for syndromic causes of autism and intellectual disability and for genes that in later development are expressed in anatomical patterns that highly correspond to the cortical midline DMN subsystem. DMN-related and DHT-affected genes (e.g., MEF2C) are involved in a number of synaptic processes, many of which impact excitation-inhibition balance. Androgens have male-specific prenatal influence over social brain circuitry in humans and may be relevant towards explaining some component of male-bias in early-onset neurodevelopmental conditions.

SUBMITTER: Lombardo MV

PROVIDER: S-EPMC7473837 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Sex-specific impact of prenatal androgens on social brain default mode subsystems.

Lombardo Michael V MV Auyeung Bonnie B Pramparo Tiziano T Quartier Angélique A Courraud Jérémie J Holt Rosemary J RJ Waldman Jack J Ruigrok Amber N V ANV Mooney Natasha N Bethlehem Richard A I RAI Lai Meng-Chuan MC Kundu Prantik P Bullmore Edward T ET Mandel Jean-Louis JL Piton Amélie A Baron-Cohen Simon S

Molecular psychiatry 20180813 9

Early-onset neurodevelopmental conditions (e.g., autism) affect males more frequently than females. Androgens may play a role in this male-bias by sex-differentially impacting early prenatal brain development, particularly neural circuits that later develop specialized roles in social cognition. Here, we find that increasing prenatal testosterone in humans is associated with later reduction of functional connectivity between social brain default mode (DMN) subsystems in adolescent males, but has ...[more]

PMID: 30104728

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Project description:Resting-state functional connectivity changes in the default mode network (DMN) of patients with major depressive disorder (MDD) have been linked to rumination. The DMN is divided into three subsystems: a midline Core, a dorsal medial prefrontal cortex (DMPFC) subsystem, and a medial temporal lobe (MTL) subsystem. We examined resting-state functional connectivity within and between DMN subsystems in MDD and its association with rumination. First, we conducted a meta-analysis on a large multi-site dataset of 618 MDD and 683 controls to quantify the differences in DMN subsystem functional connectivity between MDD and controls. Second, we tested the association of DMN subsystem functional connectivity and rumination in a sample of 115 unmedicated participants with symptoms of anxiety/depression and 48 controls. In our meta-analysis, only functional connectivity in the DMN Core was significantly reduced in MDD compared to controls (g = -0.246, CI = [-0.417; -0.074], pFDR = 0.048). Functional connectivity in the DMPFC subsystem and between the Core and DMPFC subsystems was slightly reduced but not significantly (g = -0.162, CI = [-0.310; -0.013], pFDR = 0.096; g = -0.249, CI = [-0.464; -0.034], pFDR = 0.084). Results were heterogeneous across sites for connectivity in the Core and between Core and DMPFC (I2 = 0.348 and I2 = 0.576 respectively). Prediction intervals consistently encompassed 0. In the independent sample we collected, functional connectivity within the DMN Core, DMPFC and between Core and DMPFC was not reduced in MDD compared to controls (all pFDR > 0.05). Trait rumination did not predict connectivity within and between DMN subsystems (all pFDR > 0.05). We conclude that MDD as a diagnostic category shows slightly reduced functional connectivity within the DMN Core, independent of illness duration, treatment, symptoms and trait rumination. However, this effect is small, highly variable and heterogeneous across samples, so that we could only detect it at the meta-analytic level, with a sample size of several hundreds. Our results indicate that reduced Core DMN connectivity has significant limitations as a potential clinical or prognostic marker for the diagnosis of MDD and might be more relevant to consider as a characteristic distinguishing a subgroup of individuals within this diagnostic category.

Dataset Information

Sex-specific impact of prenatal androgens on social brain default mode subsystems.

Publications

Sex-specific impact of prenatal androgens on social brain default mode subsystems.

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