Research reportSex differences in the stress response in SD rats
Introduction
Sex differences in stress responses have important implications for the vulnerability to stress-associated disorders, such as depression. The stress response of women shows significant fluctuations during the different phases of the menstrual cycle, implying that its regulation is different from that of men [1]. It was found that the activity of the hypothalamo–pituitary–adrenal (HPA) axis, a key system regulating the stress response and the autonomic responses tend to be lower in women between puberty and menopause compared to men of the same age [2]. In addition, young to middle-aged (18–45 yr) men, compared with age-matched women, show elevated levels of adrenocorticotropic hormone (ACTH) and cortisol in responses to pharmacological or physical stressors, which seems to be based upon an organizing rather than an activating effect of sex hormones [3]. On the other hand, during certain social/psychological stress tests, the HPA axis response to the stresses was more pronounced in women, although men had a higher baseline HPA activity [4], [5]. These data indicate a delicate regulating system in human, showing different patterns of sex differences in the responses to different types of stresses.
Stressful life events are one of the main precipitants of the development of major depressive disorder [6], the prevalence of which is twice as high in women as in men, particularly during a woman's reproductive age, which is characterized by fluctuating hormone levels [7]. A hyperactive HPA-axis, including the hyperactivity of the hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, was observed in depression [8], [9]. We and other groups have observed that sex hormones such as estradiol (E2) and testosterone (T) may regulate HPA activity in rat and human through their respective receptors, i.e. estrogen receptor α or β (ERα, ERβ) and androgen receptor (AR), acting directly on the CRH gene promoter. Estrogens stimulate the gene transcription of CRH, while androgens inhibit this process [8], [10], [11].
In order to investigate further the sexual dimorphic responses of stress systems, which might be the basis of sex differences seen in human mood disorder, we studied the presence of sex differences both, in acute- and chronically stressed rats, taking into consideration (i) behavioral changes after chronical stress; (ii) changes in plasma levels of corticosterone (CORT) and sex hormones (T and E2), as well as (iii) the hypothalamic mRNA-expression of stress-related molecules, including ERα, ERβ, AR, aromatase (ARO) – the key enzyme that transforms androgen into estrogen, the CORT receptors, i.e. the mineralocorticoid receptor (MR) [12] and the glucocorticoid receptor (GR) [13], and the neuropeptides CRH, arginine vasopressin (AVP) [14], [15] and oxytocin (OXT) [16]; while (iv) particular attention was paid to the stress-related molecular changes in female rats during the estrus cycle, i.e. in proestrus with the highest E2 and T levels and in diestrus with the lowest E2 and T levels [17], [18]. The paradigm of acute stress was acute electrical foot shock (FS) and the paradigm of chronic stress was chronic unpredictable mild stress (CUMS) (see below).
Section snippets
Animals
Sprague–Dawley (SD) rats of approximately 8 weeks of age with a body weight range of 220–250 g (females) or 300–330 g (males) were housed in a 12-h light–dark cycle (lights on at 08:00 h) and given food and water ad libitum. All procedures were approved by the local animal care committees in accordance with the relevant regulations and laws.
At least 3 consecutive regular estrus cycles of 4 or 5 days were monitored by taking daily vaginal smears for the female rats between 09:30 h and10:00 h. They
Effect of CUMS on estrus cycle
The estrus cycles of female CUMS rats started to prolong in the 2nd week of CUMS and prolonged with 2–6 (median = 3) days compared with the control group, especially for the diestrus stage (data not shown).
Effect of CUMS on body weight and behavior tests
The body weights of both female and male CUMS rats increased more slowly than their respective control groups, and reached significant differences in the 2nd week (p = 0.035 for females and p < 0.001 for males, respectively) and the 3rd week (p = 0.024 for females and p < 0.001 for males, respectively,
Discussion
The present study shows, for the first time in the same study, clear sex differences in FS and CUMS SD rats in terms of behavior, hormones and hypothalamic stress-related molecule expression. The main findings are (i) acute stress caused a decrease in plasma sex hormone levels (E2 and T) in female rats, but these levels remained unchanged or increased in male rats; (ii) CUMS caused in female rats, especially those in the diestrus phase, more changes than male rats in behavior and hypothalamic
Conclusion
A clear sex difference in stress response in SD rats was manifested at the level of behavior, plasma hormones and hypothalamic stress-related molecules. Female rats were more sensitive to CUMS than male rats in behavioral and hypothalamic stress-related molecular changes, and have a stronger CORT responsiveness in relation to their baseline levels than male rats following stress. In addition, acute stress caused different patterns of change in plasma sex hormone levels between male and female
Conflict of interest
The authors declare that they have no conflicts of interest.
Acknowledgements
This study was supported by the Nature Science Foundation of China (91332102 and 31271130) and supported by the Key Laboratory of Mental Disorder's Management of Zhejiang Province. The authors want to thank Mrs. W.T.P. Verweij for secretarial assistance.
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The authors contributed equally to this paper.