Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study

Sm, Wei; Eb, Baller; Kohn, Philip D.; Kippenhan, JS; Kolachana, Bhaskar; Sj, Soldin; Dr, Rubinow; Pj, Schmidt; Kf, Berman

doi:10.1038/mp.2017.72

Cited by 29 publications

(21 citation statements)

References 76 publications

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“…Opposite to controls (BDNF Val66Val), Met carriers displayed elevated PET activity in the hippocampus with E2 add-back during a working memory task. Curiously, this increase did not occur in the absence of ovarian hormones [8]. Comparative RNA-sequencing of mouse vHpc and human LCLs.…”

Section: Discussionmentioning

confidence: 96%

“…The BDNF Met genotype and ovarian steroids also interact to modulate working memory-related hippocampal function in humans [8]. A recent study examined the interaction between ovarian hormones and the Met allele in asymptomatic women.…”

Section: Discussionmentioning

confidence: 99%

“…Variation in the gene coding for brain-derived neurotrophic factor (BDNF) has been associated with estrogendependent hippocampal function, anxiety, and sex differences both in human and experimental models [5][6][7][8]. BDNF mediates the effects of estradiol (E2) in the hippocampus [9].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

et al. 2018

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Premenstrual dysphoric disorder (PMDD) affects over 5% of women, with symptoms similar to anxiety and major depression, and is associated with differential sensitivity to circulating ovarian hormones. Little is known about the genetic and epigenetic factors that increase the risk to develop PMDD. We report that 17β-estradiol (E2) affects the behavior and the epigenome in a mouse model carrying a single-nucleotide polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met), in a way that recapitulates the hallmarks of PMDD. Ovariectomized mice heterozygous for the BDNF Met allele (Het-Met) and their matched wild-type (WT) mice were administered estradiol or vehicle in drinking water for 6 weeks. Using the open field and the splash test, we show that E2 add-back induces anxiety-like and depression-like behavior in Het-Met mice, but not in WT mice. RNA-seq of the ventral hippocampus (vHpc) highlights that E2-dependent gene expression is markedly different between WT mice and Het-Met mice. Through a comparative whole-genome RNAseq analysis between mouse vHpc and lymphoblastoid cell line cultures from control women and women with PMDD, we discovered common epigenetic biomarkers that transcend species and cell types. Those genes include epigenetic modifiers of the ESC/E(Z) complex, an effector of response to ovarian steroids. Although the BDNF Met genotype intersects the behavioral and transcriptional traits of women with PMDD, we suggest that these similarities speak to the epigenetic factors by which ovarian steroids produce negative behavioral effects.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

et al. 2018

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“…Higher endogenous testosterone concentrations were found to correlate with a higher rCBF in brain regions associated with memory and attention. Recently, [ 15 O]H 2 O PET was used to investigate the correlation between a decreased production of progesterone and oestradiol by the ovaries and hippocampal working memory, although no statistically significant changes in blood flow were found …”

Section: Use Of Pet Tracers To Study Sex Steroid Hormone‐induced Chanmentioning

confidence: 99%

Sex steroid hormones and brain function:PETimaging as a tool for research

Moraga-Amaro

Waarde

Doorduin

et al. 2018

J Neuroendocrinology

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Sex steroid hormones are major regulators of sexual characteristic among species. These hormones, however, are also produced in the brain. Steroidal hormone-mediated signalling via the corresponding hormone receptors can influence brain function at the cellular level and thus affect behaviour and higher brain functions. Altered steroid hormone signalling has been associated with psychiatric disorders, such as anxiety and depression.Neurosteroids are also considered to have a neuroprotective effect in neurodegenerative diseases. So far, the role of steroid hormone receptors in physiological and pathological conditions has mainly been investigated post mortem on animal or human brain tissues. To study the dynamic interplay between sex steroids, their receptors, brain function and behaviour in psychiatric and neurological disorders in a longitudinal manner, however, noninvasive techniques are needed. Positron emission tomography (PET) is a non-invasive imaging tool that is used to quantitatively investigate a variety of physiological and biochemical parameters in vivo. PET uses radiotracers aimed at a specific target (eg, receptor, enzyme, transporter) to visualise the processes of interest. In this review, we discuss the current status of the use of PET imaging for studying sex steroid hormones in the brain. So far, PET has mainly been investigated as a tool to measure (changes in) sex hormone receptor expression in the brain, to measure a key enzyme in the steroid synthesis pathway (aromatase) and to evaluate the effects of hormonal treatment by imaging specific downstream processes in the brain. Although validated radiotracers for a number of targets are still warranted, PET can already be a useful technique for steroid hormone research and facilitate the translation of interesting findings in animal studies to clinical trials in patients. K E Y W O R D Sandrogen receptor, neuroimaging, oestrogen receptor, positron emission tomography, sex steroid hormones | INTRODUCTIONSex steroid hormones are a family of steroidal hormones that can be divided into 3 classes: oestrogens, progestins and androgens. These hormones are major regulators of sexual functions, including the reproductive cycle, reproductive physiology and the development of accessory reproductive organs.1 However, our vision of the function of these hormones has been expanded because they not only regulate sexual behaviour, but also affect brain functions, such as memory, 2 anxiety-related behaviour 3 and other functions at the cellular level. 4 Sex steroid hormones are mainly synthesised by the ovaries and testis. The hypothalamic-pituitary-gonadal (HPG) axis is the main system by which the production and release of sex steroids is regulated. 5 Circulating sex hormones can stimulate the release ofThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…In spite of the ample evidences, inconsistencies persists [28,29], in conceding the role of BDNF G196A polymorphism with mood disorders, which might also be associated with the lack of statistical power in studies of small sample size, as well as variations across studies in inclusion criteria, such as the definition of psychiatric phenotype [24,30]. Further, role of sex hormones and various other genetic, hormonal and environmental factors have been implicated in modulating BDNF function [25,29,[31][32][33][34][35]. Despite a higher risk of depression in Asian and Indian populations [25,36], extensive studies targeting polymorphisms in BDNF have never been executed in these populations so far.…”

Section: Introductionmentioning

confidence: 99%

SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population

et al. 2020

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Background: Adolescence is a distinctive stage of various changes and is noted as peak age for onset of many psychiatric disorders, especially linked to stress and depression. Several genetic variations are being increasingly known to be linked with stress and depression. The polymorphisms in two such genes, the BDNF and SLC1A3, have been reported to be linked with either depression/stress or with suicidal behaviour. These genes have not been validated in Indian population, and therefore there is a need to investigate these genes in Indian population. The present study was undertaken to test whether the known polymorphisms SLC1A3 C3590T, SLC1A3 C869G and BDNF G196A are associated or not with stress or depression in an eastern Indian population. Methods: A case-control association study was performed with 108 cases having variable levels of stress and depression and 205 matched controls. Detection of stress and depression was done by using standard instruments as PSS and CES-D, respectively and demographic profile was obtained for each individual on the basis of personal data sheet. Genotyping for the selected polymorphisms was performed by PCR followed by restriction digestion. Results: The SNP SLC1A3 C3590T was found to be associated with stress and depression (p = 0.0042, OR = 2.072). Therefore, the T allele increases the risk by more than two folds for stress and depression in the present population. The other allele of SLC1A3, G869C, as well as BDNF G196A were not associated with stress or depression in the population studied. Conclusion: SLC1A3 C3590T is a predisposition factor for stress and depression in an eastern Indian population, whereas SLC1A3 G869C and BDNF G196A were not found to be a risk factor. Therefore, presence of T allele of SLC1A3 C3590T, may predict the development of stress and depression in an individual. This may also help in the understanding of pathophysiology of the disease. However, these findings warrant a wider study in Indian populations and would be of significance in understanding the predisposition of stress and depression in this population.

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Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study

Cited by 29 publications

References 76 publications

Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

Epigenetic intersection of BDNF Val66Met genotype with premenstrual dysphoric disorder transcriptome in a cross-species model of estradiol add-back

Sex steroid hormones and brain function:PETimaging as a tool for research

SLC1A3 C3590T but not BDNF G196A is a predisposition factor for stress as well as depression, in an adolescent eastern Indian population

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