Oestrogen engages brain MC4R signalling to drive physical activity in female mice

Krause, William C.; Rodríguez, Rubén; Gegenhuber, Bruno; Matharu, Navneet; Rodriguez, Andreas N.; Padilla-Roger, Adriana M.; Toma, Kenichi; Herber, Candice B.; Correa, Stephanie M.; Duan, Xin; Ahituv, N; Tollkühn, Jessica; Ingraham, Holly A.

doi:10.1038/s41586-021-04010-3

Cited by 79 publications

(65 citation statements)

References 53 publications

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“…We asked the question whether short-term oestradiol treatment could recreate 3D genome changes observed during the high-oestrogenic, proestrus phase of the cycle. The oestrogen treatment regimen (4 h following s.c. injection of 5 g oestradiol benzoate EB) was selected based on: a) the oestrous cycle-driven oestrogen’s temporal dynamics; and b) earlier studies showing oestrogen-induced ERα genomic binding and transcription in the mouse brain within this time frame 45 . Importantly, we also confirmed that this oestrogen regimen induces changes in behaviour in cycling, low-oestrogenic (dioestrus) animals (Fig.…”

Section: Resultsmentioning

confidence: 99%

Sex-specific multi-level 3D genome dynamics in the mouse brain

et al. 2022

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The female mammalian brain exhibits sex hormone-driven plasticity during the reproductive period. Recent evidence implicates chromatin dynamics in gene regulation underlying this plasticity. However, whether ovarian hormones impact higher-order chromatin organization in post-mitotic neurons in vivo is unknown. Here, we mapped the 3D genome of ventral hippocampal neurons across the oestrous cycle and by sex in mice. In females, we find cycle-driven dynamism in 3D chromatin organization, including in oestrogen response elements-enriched X chromosome compartments, autosomal CTCF loops, and enhancer-promoter interactions. With rising oestrogen levels, the female 3D genome becomes more similar to the male 3D genome. Cyclical enhancer-promoter interactions are partially associated with gene expression and enriched for brain disorder-relevant genes and pathways. Our study reveals unique 3D genome dynamics in the female brain relevant to female-specific gene regulation, neuroplasticity, and disease risk.

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Section: Resultsmentioning

confidence: 99%

Sex-specific multi-level 3D genome dynamics in the mouse brain

et al. 2022

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“…In particular, its superior efficacy and brain permeability permit its use for oral administration. Indeed, it has been demonstrated that orally delivered DCZ effectively induces behavioral changes in mice and marmosets ( Krause et al, 2021 ; Mimura et al, 2021 ). However, the long-term chemogenetic action of DCZ remains unclear, specifically in terms of the duration of a single-dosage effect and the impact of repetitive doses over several days to weeks.…”

Section: Introductionmentioning

confidence: 99%

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

et al. 2022

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“… Oestradiol establishes neural sex differences in many vertebrates 1 – 3 and modulates mood, behaviour and energy balance in adulthood 4 – 8 . In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα) 9 .…”

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confidence: 99%

Gene regulation by gonadal hormone receptors underlies brain sex differences

Gegenhuber

Bronstein

et al. 2022

Nature

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116

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Oestradiol establishes neural sex differences in many vertebrates1–3 and modulates mood, behaviour and energy balance in adulthood4–8. In the canonical pathway, oestradiol exerts its effects through the transcription factor oestrogen receptor-α (ERα)9. Although ERα has been extensively characterized in breast cancer, the neuronal targets of ERα, and their involvement in brain sex differences, remain largely unknown. Here we generate a comprehensive map of genomic ERα-binding sites in a sexually dimorphic neural circuit that mediates social behaviours. We conclude that ERα orchestrates sexual differentiation of the mouse brain through two mechanisms: establishing two male-biased neuron types and activating a sustained male-biased gene expression program. Collectively, our findings reveal that sex differences in gene expression are defined by hormonal activation of neuronal steroid receptors. The molecular targets we identify may underlie the effects of oestradiol on brain development, behaviour and disease.

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Oestrogen engages brain MC4R signalling to drive physical activity in female mice

Cited by 79 publications

References 53 publications

Sex-specific multi-level 3D genome dynamics in the mouse brain

Sex-specific multi-level 3D genome dynamics in the mouse brain

Chronic Behavioral Manipulation via Orally Delivered Chemogenetic Actuator in Macaques

Gene regulation by gonadal hormone receptors underlies brain sex differences

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