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.

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

“…These results are not only compatible with the in-silico predictions and the in-vivo mouse rsfMRI data presented here, but is also compatible with several prior lines of work. Our prior work highlighted that DMN functional connectivity in adolescent males, but not females, is affected by heightened levels of fetal testosterone and this network was heavily comprised of MPFC and PCC 13 . In the same work, we showed that a cortical midline DMN subsystem comprising MPFC and PCC highly expresses several genes relevant for excitatory postsynaptic potentials (e.g., MEF2C, GRIK2, GRIA1, SCN3A, SCN9A, NPTX2).…”

“…In the same work, we showed that a cortical midline DMN subsystem comprising MPFC and PCC highly expresses several genes relevant for excitatory postsynaptic potentials (e.g., MEF2C, GRIK2, GRIA1, SCN3A, SCN9A, NPTX2). Importantly, the expression of these genes in human neuronal stem cells are elevated after exposure to the potent androgen DHT 13 . Thus, one potential explanation for the male-specific reduction of H in vMPFC could have to do with early developmental and androgen-sensitive upregulation of genes that play central roles in excitatory postsynaptic potentials, and thus ultimately affecting downstream E:I imbalance.…”

“…Reduced H is indicative of enhanced excitation and thus points to sex-specific dysregulation of E:I balance in social brain networks of autistic males. This malespecific dysregulation of E:I balance may be linked to sex-differential early developmental events such as androgen-upregulation of gene expression for genes that play important roles in excitatory postsynaptic potentials 13 . The intact levels of H in females may help facilitate elevated levels of compensation known as camouflaging to cope with daily social-communicative difficulties.…”

“…Having demonstrated in-silico and in-vivo that enhanced excitation reduces H in LFP and rsfMRI BOLD data, we move to application of this work to human rsfMRI data in adult autistic men and women. If E:I ratio is affected by sex-related mechanisms 13 , we predict that H would be differentially affected in autistic males versus females and manifest as sex-by-diagnosis interactions in a 2x2 factorial design (Sex: Male vs Female; Diagnosis: Autism vs Typically-Developing (TD)). Mass-univariate analysis uncovered one region in ventromedial prefrontal cortex (vMPFC) with a sex-by-diagnosis interaction passing FDR q<0.05 (F(5,104) = 15.13, p = 0.0001, partial η 2 = 0.12) ( Figure 4A).…”

“…Many highly penetrant autism-associated genes are located on the sex chromosomes (e.g., FMR1, MECP2, NLGN3, GABRA3, ARX, SYN1) and are known to lead to pathophysiology implicating E:I dysregulation 1,11,12 . Other genes playing important roles in the balance between excitation and inhibition in the brain (e.g., MEF2C, GRIK2, GRIA1, SCN3A, SCN9A, NPTX2) are highly sensitive to androgens in human neuronal stem cells and are highly expressed in 'social brain' circuitry such as the default mode network, and in particular, the medial prefrontal cortex (MPFC) 13 . Optogenetic stimulation to enhance excitation in mouse MPFC also results in changes in social behavior 14,15 .…”