Role of corticosteroid binding globulin in emotional reactivity sex differences in mice.
Psychoneuroendocrinology. 2014-12-01; 50: 252-263
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Minni AM(1), de Medeiros GF(1), Helbling JC(1), Duittoz A(2), Marissal-Arvy N(1), Foury A(1), De Smedt-Peyrusse V(1), Pallet V(3), Moisan MP(4).
(1)INRA, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France; Univ. Bordeaux, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France.
(2)Université François Rabelais, Physiologie de la Reproduction et des Comportements INRA U85, CNRS UMR7247, IFCE, 37380 Nouzilly, France.
(3)Univ. Bordeaux, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France; IPB, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France.
(4)INRA, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France; Univ. Bordeaux, Nutrition et neurobiologie intégrée, UMR 1286, 33076 Bordeaux, France. Electronic address: .
Sex differences exist for stress reactivity as well as for the prevalence of
depression, which is more frequent in women of reproductive age and often
precipitated by stressful events. In animals, the differential effect of stress
on male’s and female’s emotional behavior has been well documented. Crosstalk
between the gonadal and stress hormones, in particular between estrogens and
glucocorticoids, underlie these sex differences on stress vulnerability. We have
previously shown that corticosteroid binding globulin (CBG) deficiency in a mouse
model (Cbg k.o.) leads, in males, to an increased despair-like behavior caused by
suboptimal corticosterone stress response. Because CBG displays a sexual
dimorphism and is regulated by estrogens, we have now investigated whether it
plays a role in the sex differences observed for emotional reactivity in mice. By
analyzing Cbg k.o. and wild-type (WT) animals of both sexes, we detected sex
differences in despair-like behavior in WT mice but not in Cbg k.o. animals. We
showed through ovariectomy and estradiol (E2) replacement that E2 levels explain
the sex differences found in WT animals. However, the manipulation of E2 levels
did not affect the emotional behavior of Cbg k.o. females. As Cbg k.o. males, Cbg
k.o. females have markedly reduced corticosterone levels across the circadian
cycle and also after stress. Plasma free corticosterone levels in Cbg k.o. mice
measured immediately after stress were blunted in both sexes compared to WT mice.
A trend for higher mean levels of ACTH in Cbg k.o. mice was found for both sexes.
The turnover of a corticosterone bolus was increased in Cbg k.o. Finally, the
glucocorticoid-regulated immediate early gene early growth response 1 (Egr1)
showed a blunted mRNA expression in the hippocampus of Cbg k.o. mutants while
mineralocorticoid and glucocorticoid receptors presented sex differences but
equivalent mRNA expression between genotypes. Thus, in our experimental
conditions, sex differences for despair-like behavior in WT mice are explained by
estrogens levels. Also, in both sexes, the presence of CBG is required to attain
optimal glucocorticoid concentrations and normal emotional reactivity, although
in females this is apparent only under low E2 concentrations. These findings
suggest a complex interaction of CBG and E2 on emotional reactivity in females.