Sex-specific impact of prenatal androgens on social brain default mode subsystems.
Holt, Rosemary J
Ruigrok, Amber NV
Springer Science and Business Media LLC
MetadataShow full item record
Lombardo, M. V., Auyeung, B., Pramparo, T., Quartier, A., Courraud, J., Holt, R. J., Waldman, J., et al. (2020). Sex-specific impact of prenatal androgens on social brain default mode subsystems.. Mol Psychiatry, 25 (9), 2175-2188. https://doi.org/10.1038/s41380-018-0198-y
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.
Adolescent, Androgens, Brain, Dihydrotestosterone, Estradiol, Female, Humans, Male, Testosterone
This work was supported by a Wellcome Trust (091774/Z/10/Z) project grant to SB-C and ETB and grants from the MRC, Autism Research Trust, and the Templeton World Charitable Foundation to SBC. This work is also supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) East of England at Cambridgeshire and Peterborough NHS Foundation Trust. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. MVL and BA were supported by the Wellcome Trust. MVL was also supported by the British Academy, Jesus College Cambridge, and the European Research Council (ERC; 755816) during this period of work. AP and J-LM were supported by a grant from the Agence Nationale de la Recherche (HARTAGeNe). AQ also received additional support from a fellowship from the Fondation pour la Recherche Médicale. TP was supported by a Brain & Behavior Research Foundation (NARSAD). M-CL and AR received support from the William Binks Autism Neuroscience Fellowship at the University of Cambridge. M-CL was supported by the O’Brien Scholars Program within the Child and Youth Mental Health Collaborative at the Centre for Addiction and Mental Health and the Hospital for Sick Children, Toronto, and the Slifka-Ritvo Award for Innovation in Autism Research by the Alan B. Slifka Foundation and the International Society for Autism Research. PK was supported by the National Institutes of Health–Cambridge Scholars Program. We would like to thank Alexandra Benchoua and Laure Chatrousse from IStem, France for providing and helping with hNSC cultures.
Wellcome Trust (091774/Z/10/Z)
Medical Research Council (G0600977)
External DOI: https://doi.org/10.1038/s41380-018-0198-y
This record's URL: https://www.repository.cam.ac.uk/handle/1810/284474
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: firstname.lastname@example.org