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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    753—Neuroendocrine Anatomy and Physiology

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    753.01: Sex steroid receptor polymorphisms modulate gray matter volume in the human brain

    Location: Halls B-H

    ">*T.-V. NGUYEN1, P. J. SCHMIDT2, J. S. KIPPENHAN3, B. A. VERCHINSKI4, M. SOTTILE3, J. BLOCH3, V. EKUTA3, B. KOLACHANA4, V. MATTAY4, D. R. WEINBERGER5, K. F. BERMAN3;
    2Section of Behavioral Endocrinol., 3Section of Integrative Neuroimaging, 4Clin. Brain Disorders Br., 1Natl. Inst. of Mental Hlth., Bethesda, MD; 5Lieber Inst. of Brain Develop., Baltimore, MD

    Abstract Body: Introduction: Sex steroids have enduring organizational effects on the human brain. While animal models have identified the important role of estradiol and progesterone in neuroplasticity and genetic association studies have linked single nucleotide polymorphisms (SNPs) in the genes for estrogen receptors alpha (ESR1) and beta (ESR2) and the progesterone receptor (PGR) to sexually dimorphic psychiatric disorders, the neural correlates of these polymorphisms have not been well characterized in the human brain.
    Methods: We acquired 1.5T T1-weighted SPGR MRI scans for 289 healthy right-handed subjects (157 females) aged 18-55 years old (mean=33 +/- 10), and analyzed voxelwise Jacobian-modulated gray matter volumes (GMV) obtained from SPM8-based segmentation and DARTEL-based spatial normalization. DNA was isolated from peripheral blood samples, and genotypes for ESR1 (rs2234693, rs9340799), ESR2 (rs1256049, rs4986938) and PGR (rs10895068) SNPs were determined with 5'exonuclease Taqman allelic discrimination assay. Using voxelwise ANOVAs and linear regression models while controlling for age and total brain volume (p<0.001), we tested for main effects of sex and genetic variation in ESR1,ESR2, and PGR, and for sex-by-genotype interactions in areas where there was a significant main effect of sex. Results: Females had increased relative GMV bilaterally in the frontal and parietal lobes, whereas males had increased relative GMV bilaterally in the temporal, occipital and posterior lobes of the cerebellum. ESR1, ESR2 and PGR genotypes that are linked to increased receptor expression were associated with increased GMV in a number of sexually dimorphic and non-sexually dimorphic brain regions. The interaction analysis revealed that ESR1 genotypes were associated with "feminization" (increased GMV) of the medial orbitofrontal cortex (p=4 x 10-6) and left inferior parietal lobule (p=10-5) in females, and with "masculinization" (decreased GMV) of these areas in males; ESR2 genotypes were associated with "feminization" (decreased GMV) of the temporal poles (p=4 x 10-6)and the posterior lobe of the cerebellum in females (p=2 x 10-6), and with "masculinization" (increased GMV) of these areas in males.
    Conclusions: Genotypic variances of ESR1, ESR2, and PGR modulate GMV across the brain. Moreover, ESR1/ESR2 polymorphisms are associated with masculinization and feminization of specific brain regions. These data suggest mechanisms through which sex steroid receptors may contribute to the neural underpinnings of sexually dimorphic behavior and brain function.

    Lay Language Summary: Genetic Variation in Hormone Receptors Changes the Structure of the Human Brain
    Our research indicates that common genetic variation in the receptors for the sex hormones estrogen and progesterone are accompanied by local changes in the structure of the human brain.  These findings, shown here for the first time using neuroimaging in healthy living adults, highlight potential mechanisms through which hormones affect brain structure in an enduring way and may lead to sex differences in thought and behavior and in susceptibility to some neuropsychiatric disorders such as depression, Alzheimer’s disease, multiple sclerosis, and schizophrenia.
    Sex differences in cognition and in the manifestations of neuropsychiatric disorders have long been documented.  For example, men on average tend to excel at visuospatial tasks while women have better verbal and emotional processing skills; in addition, there are sex differences in the age of onset as well as the course and severity of several neuropsychiatric disorders.  Yet it is also evident that even within one gender, there is tremendous variability, with some men showing a more “feminine” pattern and some women showing a more “masculine” pattern of thought, behavior and disease severity.  While environmental experiences are likely to play a significant role in this variability, hormones represent a compelling biological mechanism through which characteristics in the human brain may be modulated and thus confer sex differences.  Yet the exact processes through which this may occur remain elusive.  We show here that changes in brain structure related to common variations in the genes for hormone receptors represent an important process through which hormones may modulate variability in human thought, behavior and neuropsychiatric disorders.
    To explore the relationship between genetic features and brain structure, we determined the genetic makeup of 289 adults 18 to 55 years old with a focus on variations of single nucleotides in genes that code for hormone receptors.  We also collected brain images of these same individuals using magnetic resonance imaging and we determined how much gray matter was present in each person’s cerebral cortex as well as in non-cortical structures such as the hippocampus, cerebellum and the basal ganglia.
    Consistent with the hypothesis that sex hormones are associated with increased brain growth, we found that common variations linked to increased estrogen/progesterone receptor gene expression were associated with increased gray matter volume in several frontal, temporal, parietal and occipital brain regions, as well as in non-cortical structures such as the hippocampus, cerebellum and basal ganglia in both men and women.  Common variations linked to increased estrogen receptor gene expression were also associated with a more “masculine” brain structure in men (closer to the average male brain) and a more “feminine” brain structure in women (closer to the average female brain) in specific regions of the frontal, parietal and temporal lobes as well as the cerebellum.
    In summary, we show here that common variation in the genes for hormone receptors affect brain structure in both men and women. We also demonstrate that hormone receptors contribute to a more “masculine” or more “feminine” brain structure in key brain regions implicated in language, emotional regulation, and visuospatial skills. These findings provide insight into the mechanisms through which hormones regulate male and female brain function and offer a framework within which to understand the neural basis of sex differences in behavior, cognition, and brain disorders.

    Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    753—Neuroendocrine Anatomy and Physiology

    Wednesday, November 13, 2013, 8:00 am - 12:00 noon

    753.01: Sex steroid receptor polymorphisms modulate gray matter volume in the human brain

    Location: Halls B-H

    ">*T.-V. NGUYEN1, P. J. SCHMIDT2, J. S. KIPPENHAN3, B. A. VERCHINSKI4, M. SOTTILE3, J. BLOCH3, V. EKUTA3, B. KOLACHANA4, V. MATTAY4, D. R. WEINBERGER5, K. F. BERMAN3;
    2Section of Behavioral Endocrinol., 3Section of Integrative Neuroimaging, 4Clin. Brain Disorders Br., 1Natl. Inst. of Mental Hlth., Bethesda, MD; 5Lieber Inst. of Brain Develop., Baltimore, MD

    Abstract Body: Introduction: Sex steroids have enduring organizational effects on the human brain. While animal models have identified the important role of estradiol and progesterone in neuroplasticity and genetic association studies have linked single nucleotide polymorphisms (SNPs) in the genes for estrogen receptors alpha (ESR1) and beta (ESR2) and the progesterone receptor (PGR) to sexually dimorphic psychiatric disorders, the neural correlates of these polymorphisms have not been well characterized in the human brain.
    Methods: We acquired 1.5T T1-weighted SPGR MRI scans for 289 healthy right-handed subjects (157 females) aged 18-55 years old (mean=33 +/- 10), and analyzed voxelwise Jacobian-modulated gray matter volumes (GMV) obtained from SPM8-based segmentation and DARTEL-based spatial normalization. DNA was isolated from peripheral blood samples, and genotypes for ESR1 (rs2234693, rs9340799), ESR2 (rs1256049, rs4986938) and PGR (rs10895068) SNPs were determined with 5'exonuclease Taqman allelic discrimination assay. Using voxelwise ANOVAs and linear regression models while controlling for age and total brain volume (p<0.001), we tested for main effects of sex and genetic variation in ESR1,ESR2, and PGR, and for sex-by-genotype interactions in areas where there was a significant main effect of sex. Results: Females had increased relative GMV bilaterally in the frontal and parietal lobes, whereas males had increased relative GMV bilaterally in the temporal, occipital and posterior lobes of the cerebellum. ESR1, ESR2 and PGR genotypes that are linked to increased receptor expression were associated with increased GMV in a number of sexually dimorphic and non-sexually dimorphic brain regions. The interaction analysis revealed that ESR1 genotypes were associated with "feminization" (increased GMV) of the medial orbitofrontal cortex (p=4 x 10-6) and left inferior parietal lobule (p=10-5) in females, and with "masculinization" (decreased GMV) of these areas in males; ESR2 genotypes were associated with "feminization" (decreased GMV) of the temporal poles (p=4 x 10-6)and the posterior lobe of the cerebellum in females (p=2 x 10-6), and with "masculinization" (increased GMV) of these areas in males.
    Conclusions: Genotypic variances of ESR1, ESR2, and PGR modulate GMV across the brain. Moreover, ESR1/ESR2 polymorphisms are associated with masculinization and feminization of specific brain regions. These data suggest mechanisms through which sex steroid receptors may contribute to the neural underpinnings of sexually dimorphic behavior and brain function.

    Lay Language Summary: Genetic Variation in Hormone Receptors Changes the Structure of the Human Brain
    Our research indicates that common genetic variation in the receptors for the sex hormones estrogen and progesterone are accompanied by local changes in the structure of the human brain.  These findings, shown here for the first time using neuroimaging in healthy living adults, highlight potential mechanisms through which hormones affect brain structure in an enduring way and may lead to sex differences in thought and behavior and in susceptibility to some neuropsychiatric disorders such as depression, Alzheimer’s disease, multiple sclerosis, and schizophrenia.
    Sex differences in cognition and in the manifestations of neuropsychiatric disorders have long been documented.  For example, men on average tend to excel at visuospatial tasks while women have better verbal and emotional processing skills; in addition, there are sex differences in the age of onset as well as the course and severity of several neuropsychiatric disorders.  Yet it is also evident that even within one gender, there is tremendous variability, with some men showing a more “feminine” pattern and some women showing a more “masculine” pattern of thought, behavior and disease severity.  While environmental experiences are likely to play a significant role in this variability, hormones represent a compelling biological mechanism through which characteristics in the human brain may be modulated and thus confer sex differences.  Yet the exact processes through which this may occur remain elusive.  We show here that changes in brain structure related to common variations in the genes for hormone receptors represent an important process through which hormones may modulate variability in human thought, behavior and neuropsychiatric disorders.
    To explore the relationship between genetic features and brain structure, we determined the genetic makeup of 289 adults 18 to 55 years old with a focus on variations of single nucleotides in genes that code for hormone receptors.  We also collected brain images of these same individuals using magnetic resonance imaging and we determined how much gray matter was present in each person’s cerebral cortex as well as in non-cortical structures such as the hippocampus, cerebellum and the basal ganglia.
    Consistent with the hypothesis that sex hormones are associated with increased brain growth, we found that common variations linked to increased estrogen/progesterone receptor gene expression were associated with increased gray matter volume in several frontal, temporal, parietal and occipital brain regions, as well as in non-cortical structures such as the hippocampus, cerebellum and basal ganglia in both men and women.  Common variations linked to increased estrogen receptor gene expression were also associated with a more “masculine” brain structure in men (closer to the average male brain) and a more “feminine” brain structure in women (closer to the average female brain) in specific regions of the frontal, parietal and temporal lobes as well as the cerebellum.
    In summary, we show here that common variation in the genes for hormone receptors affect brain structure in both men and women. We also demonstrate that hormone receptors contribute to a more “masculine” or more “feminine” brain structure in key brain regions implicated in language, emotional regulation, and visuospatial skills. These findings provide insight into the mechanisms through which hormones regulate male and female brain function and offer a framework within which to understand the neural basis of sex differences in behavior, cognition, and brain disorders.