Epigenetic mechanisms underlying sex differences in the brain and behavior

Kundakovic, Marija; Tickerhoof, Maria

doi:10.1016/j.tins.2023.09.007

Cited by 7 publications

(9 citation statements)

References 147 publications

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“…Oestrous cycle tracking was performed using vaginal smear cytology, a well-established method, as described previously 1-3 . Smears were collected by filling a disposable transfer pipette with 100 µl of distilled water, gently placing the tip of the pipette at the vaginal opening and collecting cells via lavage.…”

Section: Methodsmentioning

confidence: 99%

“…Sex-specific characteristics of the brain are dynamically shaped throughout life, as a result of the actions of gonadal hormones, sex chromosomes, and the environment 1,4 . During the reproductive period in females, cycling ovarian hormones, oestrogens and progesterone, play a critical role in brain plasticity relevant to reproductive and non-reproductive behaviours including mating, feeding 10,11 , learning 12,13 , reward processing 14,15 , and anxiety- and depression-related behaviours 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…So far, molecular studies in neuroscience have focused on the male brain 8 , and our knowledge of sex-specific molecular mechanisms in the brain is therefore limited 1 . It has been assumed that a specific group of transcription factors, known as immediate early gene (IEG) products, drive chromatin 17 and synaptic 18 plasticity across sexes, yet the molecular basis of sex differences in synaptic and behavioural plasticity remains obscure.…”

Section: Introductionmentioning

confidence: 99%

“… Sex differences are found in brain structure and function across species, and across brain disorders in humans 1-3 . The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan 4 .…”

mentioning

confidence: 99%

“…Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation 1 in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.…”

mentioning

confidence: 99%

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Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Rocks,

Purisic,

Gallo

et al. 2023

Preprint

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Sex differences are found in brain structure and function across species, and across brain disorders in humans1-3. The major source of brain sex differences is differential secretion of steroid hormones from the gonads across the lifespan4. Specifically, ovarian hormones oestrogens and progesterone are known to dynamically change structure and function of the adult female brain, having a major impact on psychiatric risk5-7. However, due to limited molecular studies in female rodents8, very little is still known about molecular drivers of female-specific brain and behavioural plasticity. Here we show that overexpressing Egr1, a candidate oestrous cycle-dependent transcription factor9, induces sex-specific changes in ventral hippocampal neuronal chromatin, gene expression, and synaptic plasticity, along with hippocampus-dependent behaviours. Importantly, Egr1 overexpression mimics the high-oestrogenic phase of the oestrous cycle, and affects behaviours in ovarian hormone-depleted females but not in males. We demonstrate that Egr1 opens neuronal chromatin directly across the sexes, although with limited genomic overlap. Our study not only reveals the first sex-specific chromatin regulator in the brain, but also provides functional evidence that this sex-specific gene regulation drives neuronal gene expression, synaptic plasticity, and anxiety- and depression-related behaviour. Our study exemplifies an innovative sex-based approach to studying neuronal gene regulation1in order to understand sex-specific synaptic and behavioural plasticity and inform novel brain disease treatments.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Rocks,

Purisic,

Gallo

et al. 2023

Preprint

Self Cite

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Sex differences in mechanisms of pain hypersensitivity

Mogil,

Parisien,

Esfahani

et al. 2024

Neuroscience & Biobehavioral Reviews

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Exposure to prenatal excess or imbalanced micronutrients leads to long‐term perturbations in one‐carbon metabolism, trimethylamine‐N‐oxide and DNA methylation in Wistar rat offspring

Shelp,

Dong,

Orlov

et al. 2024

The FASEB Journal

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Prenatal multivitamins, including folic acid, are commonly consumed in excess, whereas choline, an essential nutrient and an important source of labile methyl groups, is underconsumed. Here, we characterized profiles of one‐carbon metabolism and related pathways and patterns of DNA methylation in offspring exposed to excess or imbalanced micronutrients prenatally. Pregnant Wistar rats were fed either recommended 1× vitamins (RV), high 10× vitamins (HV), high 10× folic acid with recommended choline (HFolRC), or high 10× folic acid with no choline (HFolNC). Offspring were weaned to a high‐fat diet for 12 weeks. Circulating metabolites were analyzed with a focus on the hypothalamus, an area known to be under epigenetic regulation. HV, HFolRC, and HFolNC males had higher body weight (BW) and lower plasma choline and methionine consistent with lower hypothalamic S‐adenosylmethionine (SAM):S‐adenosylhomocysteine (SAH) and global DNA methylation compared with RV. HV and HFolNC females had higher BW and lower plasma 5‐methyltetrahydrofolate and methionine consistent with lower hypothalamic global DNA methylation compared with RV. Plasma dimethylglycine (DMG) and methionine were higher as with hypothalamic SAM:SAH and global DNA methylation in HFolRC females without changes in BW compared with RV. Plasma trimethylamine and trimethylamine‐N‐oxide were higher in males but lower in females from HFolRC compared with RV. Network modeling revealed a link between the folate‐dependent pathway and SAH, with most connections through DMG. Final BW was negatively correlated with choline, DMG, and global DNA methylation. In conclusion, prenatal intake of excess or imbalanced micronutrients induces distinct metabolic and epigenetic perturbations in offspring that reflect long‐term nutritional programming of health.

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Epigenetic mechanisms underlying sex differences in the brain and behavior

Cited by 7 publications

References 147 publications

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Egr1 is a sex-specific regulator of neuronal chromatin, synaptic plasticity, and behaviour

Sex differences in mechanisms of pain hypersensitivity

Exposure to prenatal excess or imbalanced micronutrients leads to long‐term perturbations in one‐carbon metabolism, trimethylamine‐N‐oxide and DNA methylation in Wistar rat offspring

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