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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

Molecular Psychiatry volume 23, pages 1066–1075 (2018)Cite this article

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Abstract

Preclinical evidence suggests that the actions of ovarian steroid hormones and brain-derived neurotrophic factor (BDNF) are highly convergent on brain function. Studies in humanized mice document an interaction between estrus cycle-related changes in estradiol secretion and BDNF Val66Met genotype on measures of hippocampal function and anxiety-like behavior. We believe our multimodal imaging data provide the first demonstration in women that the effects of the BDNF Val/Met polymorphism on hippocampal function are selectively modulated by estradiol. In a 6-month pharmacological hormone manipulation protocol, healthy, regularly menstruating, asymptomatic women completed positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) scans while performing the n-back working memory task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist, leuprolide acetate; leuprolide plus estradiol; and leuprolide plus progesterone. For each of the three hormone conditions, a discovery data set was obtained with oxygen-15 water regional cerebral blood flow PET in 39 healthy women genotyped for BDNF Val66Met, and a confirmatory data set was obtained with fMRI in 27 women. Our results, in close agreement across the two imaging platforms, demonstrate an ovarian hormone-by-BDNF interaction on working memory-related hippocampal function (PET: F2,37=9.11, P=0.00026 uncorrected, P=0.05, familywise error corrected with small volume correction; fMRI: F2,25=5.43, P=0.01, uncorrected) that reflects differential hippocampal recruitment in Met carriers but only in the presence of estradiol. These findings have clinical relevance for understanding the neurobiological basis of individual differences in the cognitive and behavioral effects of ovarian steroids in women, and may provide a neurogenetic framework for understanding neuropsychiatric disorders related to reproductive hormones as well as illnesses with sex differences in disease expression and course.

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Acknowledgements

We thank the National Institutes of Health 2013 Bench-to-Bedside award program (290698), the Positron Emission Tomography Department, and the Functional Magnetic Resonance Imaging Core Facility of the National Institutes of Health for their help and support. This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; NIH protocols: NCT00004571, NCT00001258 and NCT00001322; NIMH project #: ZIAMH002717 and ZIAMH002874.

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  1. P J Schmidt and K F Berman: These authors contributed equally to this work.

Authors and Affiliations

  1. Section on Integrative Neuroimaging, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA

    S-M Wei, P D Kohn, J S Kippenhan & K F Berman

  2. Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA

    S-M Wei, P D Kohn, J S Kippenhan, B Kolachana & K F Berman

  3. Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA

    E B Baller

  4. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    S J Soldin

  5. Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    D R Rubinow

  6. Section on Behavioral Endocrinology, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, MD, USA

    P J Schmidt

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Wei, SM., Baller, E., Kohn, P. et al. Brain-derived neurotrophic factor Val66Met genotype and ovarian steroids interactively modulate working memory-related hippocampal function in women: a multimodal neuroimaging study. Mol Psychiatry 23, 1066–1075 (2018). https://doi.org/10.1038/mp.2017.72

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