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Brain-derived neurotrophic factor Val⁶⁶Met polymorphism affects resting regional cerebral blood flow and functional connectivity differentially in women versus men.

Abstract

The human Val⁶⁶Met single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene impacts BDNF signaling at the cellular level. At the neural-systems level, it is associated with differences in prefrontal cortex (PFC) and hippocampal function during performance of cognitive and affective tasks. Because the impact of this variant on basal prefrontal and hippocampal activity is not known but may be relevant to understanding the function of this gene in health and disease, we studied 94 healthy individuals with H₂ ¹⁵O PET to assess regional cerebral blood flow (rCBF) during rest and tested for between-genotype differences. Because BDNF and gonadal steroid hormones conjointly influence neuronal growth, survival, and plasticity in hippocampus and PFC, we also tested for sex × genotype interactions. Finally, in light of the known impact of BDNF on plasticity and dendritic arborization, we complimented direct rCBF comparisons with connectivity analyses to determine how activity in hippocampal and prefrontal regions showing between-genotype group differences covaries with rCBF in other nodes throughout the brain in a genotype- or sex-dependent manner. Compared with Val homozygotes, Met carriers had higher rCBF in prefrontal (BA25 extending into BA10) and hippocampal/parahippocampal regions. Moreover, there were significant sex × genotype interactions in regions (including frontal, parahippocampal, and lateral temporal cortex) in which Val homozygotes showed higher rCBF in females than males, but Met carriers showed the opposite relationship. Functional connectivity analysis demonstrated that correlations of BA25, hippocampus, and parahippocampus with frontal and temporal networks were positive for Val homozygotes and negative for Met carriers. In addition, sex × genotype analysis of functional connectivity revealed that genotype affected directionality of the inter-regional correlations differentially in men versus women. Our data indicate that BDNF allelic variation and sex interactively affect basal prefrontal and hippocampal function.

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  • Authors

    Wei SM, Eisenberg DP, Kohn PD, Kippenhan JS, Kolachana BS, Weinberger DR, Berman KF

    Institution

    Section on Integrative Neuroimaging, National Institute of Mental Health Intramural Research Programs, National Institutes of Health, Bethesda, Maryland 20892, USA.

    Source

    The Journal of neuroscience : the official journal of the Society for Neuroscience 32:20 2012 May 16 pg 7074-81

    MeSH

    Adolescent
    Adult
    Alleles
    Brain-Derived Neurotrophic Factor
    Cerebrovascular Circulation
    Female
    Functional Neuroimaging
    Genotype
    Hippocampus
    Humans
    Male
    Middle Aged
    Neural Pathways
    Oxygen Radioisotopes
    Polymorphism, Single Nucleotide
    Positron-Emission Tomography
    Prefrontal Cortex
    Sex Characteristics
    Temporal Lobe

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Intramural

    Language

    eng

    PubMed ID

    22593075