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      Sex-related factors influence expression of mood-related genes in the basolateral amygdala differentially depending on age and stress exposure

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      1 , 2 , 1 , 2 , 1 , 2 ,
      Biology of Sex Differences
      BioMed Central

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          Abstract

          Background

          Women are twice as likely to be diagnosed with major depressive disorder (MDD) compared to men, but the molecular mechanisms underlying this sex difference are unclear. Previous studies in the human postmortem brain suggest dysfunction in basolateral amygdala (BLA) inhibitory gamma-aminobutyric acid (GABA) signaling and brain-derived neurotrophic factor (BDNF) function, specifically in females with MDD.

          Methods

          We investigated the effects of sex chromosome complement, developmental gonadal sex, and circulating testosterone on expression of 3 GABA-related and 2 BDNF-related genes in the BLA using three cohorts of four core genotypes (FCG) mice. Cohort 1 included gonadally intact pre-pubertal FCG mice; results were analyzed using two-way ANOVA (sex chromosome complement-by-gonadal sex). We examined the same genes under adult non-stressed (cohort 2) and chronically stressed conditions (cohort 3). The results for cohorts 2 and 3 were analyzed by three-way ANOVA (sex chromosome complement-by-gonadal sex-by-hormone). The use of heatmaps and Spearman correlation of BLA gene expression and anxiety-like behavior provides a global interpretation of gene expression patterns.

          Results

          In weanlings, we found an effect of sex chromosome complement, with lower expression of GABA/BDNF-related genes in XY mice. Most of these effects did not persist into adulthood, although a number of interesting interactions between organizational and activational effects of hormones emerged. In our adult cohorts, we found that testosterone had different effects depending on stress conditions and/or gonadal sex. Notably, in our chronically stressed adults, we found that the BLA pattern of gene expression for the GABA-related gene, somatostatin ( Sst), matched the anxiety-like behavior pattern (i.e., lower Sst and higher anxiety-like behavior in XY mice, while testosterone increased Sst and decreased anxiety-like behavior). Additionally, increased Sst gene expression was correlated with decreased anxiety-like behavior.

          Conclusions

          Sex chromosome complement is an important factor modulating expression of mood-related genes during pre-pubertal development. The observed sex differences under chronically stressed conditions suggest that different molecular profiles may characterize male and female MDD. Our findings here for Sst are especially interesting, and suggest an underlying XY vulnerability that is typically compensated for by circulating testosterone in “normal” males. Without testosterone, women may have lower SST expression in the amygdala, resulting in increased MDD vulnerability.

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          Most cited references45

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          Major depressive disorder.

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            Reframing sexual differentiation of the brain.

            In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.
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              Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression.

              Measurement of cortical gamma-aminobutyric acid (GABA) and glutamate concentrations is possible using proton magnetic resonance spectroscopy. An initial report, using this technique, suggested that occipital cortex GABA concentrations are reduced in patients with major depressive disorder (MDD) relative to healthy comparison subjects. To replicate the GABA findings in a larger sample of MDD patients, to examine the clinical correlates of the GABA reductions in these subjects, and to examine other critical metabolite levels. Study for association. Academic clinical research program. The GABA measurements were made on 38 healthy control subjects and 33 depressed subjects. Occipital cortex metabolite levels were measured using proton magnetic resonance spectroscopy. The levels of occipital cortex GABA, glutamate, N-acetylaspartate, aspartate, creatine, and choline-containing compounds, along with several measures of tissue composition, were compared between the 2 groups. Depressed subjects had significantly lower occipital cortex GABA concentrations compared with healthy controls (P =.01). In addition, mean glutamate levels were significantly increased in depressed subjects compared with healthy controls (P<.001). Significant reductions in the percentage of solid tissue (P =.009) and the percentage of white matter (P =.04) in the voxel were also observed. An examination of a combined database including subjects from the original study suggests that GABA and glutamate concentrations differ among MDD subtypes. The study replicates the findings of decreased GABA concentrations in the occipital cortex of subjects with MDD. It also demonstrates that there is a change in the ratio of excitatory-inhibitory neurotransmitter levels in the cortex of depressed subjects that may be related to altered brain function. Last, the combined data set suggests that magnetic resonance spectroscopy GABA measures may serve as a biological marker for a subtype of MDD.
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                Author and article information

                Contributors
                rfp3@pitt.edu
                gmv8@pitt.edu
                seneyml@upmc.edu
                Journal
                Biol Sex Differ
                Biol Sex Differ
                Biology of Sex Differences
                BioMed Central (London )
                2042-6410
                17 September 2016
                17 September 2016
                2016
                : 7
                : 50
                Affiliations
                [1 ]Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213 USA
                [2 ]Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA 15213 USA
                Article
                106
                10.1186/s13293-016-0106-6
                5027117
                46516f92-6d26-474f-9034-ef10bec5afa9
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 July 2016
                : 9 September 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000025, National Institute of Mental Health;
                Award ID: MH103473
                Funded by: FundRef http://dx.doi.org/10.13039/100000874, Brain and Behavior Research Foundation;
                Award ID: FSZ00207
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Human biology
                Human biology

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