Effect of castration and testosterone in experimental models of depression in mice.

Bernardi, Maria Martha; Genedani, Susanna; Tagliavini, Simonetta; Bertolini, Alfio

doi:10.1037/0735-7044.103.5.1148

Cited by 35 publications

(16 citation statements)

References 12 publications

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“…Activational effects of TP in the absence of postnatal TP reduced female time spent immobile, resulting in a masculinized response. These data are in agreement with previous work showing that after gonadectomy, TP replacement in males reduces immobile time in this test (43). Postnatal TP treatment did not result in a change in immobile time, and surprisingly, mice exposed to both organizational and activational TP were not masculinized in their behavior as we had expected.…”

Section: Discussionsupporting

confidence: 95%

“…Gonadal hormones are influential in early brain development through organizational effects as well as in modulation of adult physiology and behavior through activational effects. Testosterone plays an important role in suppressing the HPA stress axis and in increasing active behavioral responses to environmental challenges in males (4,43,44), contributing to sex differences in stress responsivity. We sought to examine whether female physiological and behavioral stress responses could be masculinized by organizational and/or activational effects of testosterone by administration of TP as a single injection on PN 1 or as a sc implant beginning at puberty.…”

Section: Discussionmentioning

confidence: 99%

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Organizational and Activational Effects of Testosterone on Masculinization of Female Physiological and Behavioral Stress Responses

Goel

Bale

2008

Endocrinology

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The prevalence of affective disorders is two times greater in women than in men. The onset of anxiety and depression occurs at different ages that may correspond to key developmental periods when the brain is more vulnerable to hormonal and exogenous influences. Because stressful life events can precipitate disease onset, the development of greater stress sensitivity in females may contribute to their increased vulnerability. Gonadal hormone exposure in males during early development and again from puberty onward plays a prominent role in sexually dimorphic brain formation, possibly contributing to sex differences in stress responsivity. Therefore, organizational effects of testosterone propionate (TP) administered postnatally and activational effects of TP administered beginning at puberty on adult female physiological and behavioral stress responses were examined in mice. Although the activational effects of TP in females ameliorated the sex difference in the hypothalamic-pituitary-adrenal axis stress response, there was no effect of postnatal TP. Similarly, higher immobile time in intact females in the tail suspension test was blunted by activational TP in the absence of postnatal TP. However, in the marble-burying test of anxiety-like behaviors, organizational and activational TP independently resulted in increased burying behaviors. These results show that TP administration has distinct effects on reducing physiological and behavioral stress responsivity in rodent models and suggest that sex differences in these responses may partially result from the absence of testosterone in females.

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Section: Discussionsupporting

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Organizational and Activational Effects of Testosterone on Masculinization of Female Physiological and Behavioral Stress Responses

Goel

Bale

2008

Endocrinology

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“…Other potential limitations to the design of this study are that we do not have a group of mice that was gonadectomized with estradiol and progesterone replacement and we do not examine gene expression under baseline (i.e., non-stress) conditions. Evidence suggests that testosterone reduces anxiety-like behaviors [72-75]; on the other hand, estradiol exposure has been reported to both increase and decrease anxiety-like behavior [76-78]. We chose to perform testosterone rather than estradiol replacement based on the more consistent reported results for testosterone on anxiety-like behavior [72-75].…”

Section: Discussionmentioning

confidence: 99%

Sex chromosome complement regulates expression of mood-related genes

et al. 2013

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BackgroundStudies on major depressive and anxiety disorders suggest dysfunctions in brain corticolimbic circuits, including altered gamma-aminobutyric acid (GABA) and modulatory (serotonin and dopamine) neurotransmission. Interestingly, sexual dimorphisms in GABA, serotonin, and dopamine systems are also reported. Understanding the mechanisms behind these sexual dimorphisms may help unravel the biological bases of the heightened female vulnerability to mood disorders. Here, we investigate the contribution of sex-related factors (sex chromosome complement, developmental gonadal sex, or adult circulating hormones) to frontal cortex expression of selected GABA-, serotonin-, and dopamine-related genes.MethodsAs gonadal sex is determined by sex chromosome complement, the role of sex chromosomes cannot be investigated individually in humans. Therefore, we used the Four Core Genotypes (FCG) mouse model, in which sex chromosome complement and gonadal sex are artificially decoupled, to examine the expression of 13 GABA-related genes, 6 serotonin- and dopamine-related genes, and 8 associated signal transduction genes under chronic stress conditions. Results were analyzed by three-way ANOVA (sex chromosome complement × gonadal sex × circulating testosterone). A global perspective of gene expression changes was provided by heatmap representation and gene co-expression networks to identify patterns of transcriptional activities related to each main factor.ResultsWe show that under chronic stress conditions, sex chromosome complement influenced GABA/serotonin/dopamine-related gene expression in the frontal cortex, with XY mice consistently having lower gene expression compared to XX mice. Gonadal sex and circulating testosterone exhibited less pronounced, more complex, and variable control over gene expression. Across factors, male conditions were associated with a tightly co-expressed set of signal transduction genes.ConclusionsUnder chronic stress conditions, sex-related factors differentially influence expression of genes linked to mood regulation in the frontal cortex. The main factor influencing expression of GABA-, serotonin-, and dopamine-related genes was sex chromosome complement, with an unexpected pro-disease effect in XY mice relative to XX mice. This effect was partially opposed by gonadal sex and circulating testosterone, although all three factors influenced signal transduction pathways in males. Since GABA, serotonin, and dopamine changes are also observed in other psychiatric and neurodegenerative disorders, these findings have broader implications for the understanding of sexual dimorphism in adult psychopathology.

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“…For instance, in male rodents, testosterone modulates anxiety-like behavior (Aikey et al, 2002;Fernandez-Guasti and Martinez-Mota, 2005;Frye and Seliga, 2001;Toufexis et al, 2005), depressive-like behavior (Bernardi et al, 1989;Buddenberg et al, 2009;Carrier and Kabbaj, 2012;Frye and Walf, 2009), the reactivity of the hypothalamic-pituitary-adrenal axis (Foilb et al, 2011;Goel et al, 2011;Handa et al, 1994;McCormick et al, 2002;Seale et al, 2004;Viau and Meaney, 1996), food intake (Gentry and Wade, 1976) and body weight gain (Gentry and Wade, 1976;Wainwright et al, 2011). With this in mind, it is rather surprising that the effects of testosterone on spatial tasks that are not motivated by either food reward or water escape have gone almost completely unexplored (McConnell et al, 2012).…”

Section: Introductionmentioning

confidence: 95%