Sex-specific mechanisms for responding to stress

Abstract

Posttraumatic stress disorder and major depression share stress as an etiological contributor and are more common in women than in men. Traditionally, preclinical studies investigating the neurobiological underpinnings of stress vulnerability have used only male rodents; however, recent studies that include females are finding sex-specific mechanisms for responding to stress. This Mini-Review examines recent literature using a framework developed by McCarthy and colleagues (2012; J Neurosci 32:2241-2247) that highlights different types of sex differences. First, we detail how learned fear responses in rats are sexually dimorphic. Then, we contrast this finding with fear extinction, which is similar in males and females at the behavioral level but at the circuitry level is associated with sex-specific cellular changes and, thus, exemplifies a sex convergence. Next, sex differences in stress hormones are detailed. Finally, the effects of stress on learning, attention, and arousal are used to highlight the concept of a sex divergence in which the behavior of males and females is similar at baseline but diverges following stressor exposure. We argue that appreciating and investigating the diversity of sex differences in stress response systems will improve our understanding of vulnerability and resilience to stress-related psychiatric disorders and likely lead to the development of novel therapeutics for better treatment of these disorders in both men and women. © 2016 Wiley Periodicals, Inc.

Keywords: arousal; attention; corticotropin releasing hormone; depression; fear conditioning; glucocorticoids; posttraumatic stress disorder; sexual dimorphism.

Figure 1

Depiction of various sex differences based on McCarthy et al. (2012). Males are illustrated with blue and females are illustrated with red. A) A sexual dimorphism is when an endpoint takes two forms, one that is prevalent in males and another that is prevalent in females. B) A sex convergence is when the endpoint is similar in males and females, but the underlying mechanisms are different. C) A sex difference is when an endpoint exists on the same continuum in both sexes but the endpoints on average are different for males compared to females. Note that here we have illustrated the female mean as higher than the male mean, but of course the opposite could also be true. D) A sex divergence is when a sex difference emerges after an event, such as a stressor. Although in this depiction the stressor causes an increase in the endpoint in females and a decrease in the endpoint in males, the opposite can also occur. Moreover, in some cases, stress causes the endpoint to change in a similar direction for both males and females, but the magnitude of the effect is greater in one sex than the other.

Figure 2

Illustration depicting the learned fear responses of freezing and darting. These responses are sexually dimorphic because they are two different forms of behavior and darting occurs more frequently in female than male rats.

Figure 3

The effect of CRF on sustained attention and its underlying circuitry is mediated by ovarian hormones. (A) CRF (0.5 μg, intracerebroventricular administration) impairs the vigilance index, an overall measure of sustained attention, in males and diestrous females, but not estrous/proestrous females. Reproduced with permission from Cole et al., (2016). (B) CRF activates the nucleus basalis of Meynet (nbM) and infralimbic cortex (IL) sustained attention circuitry in all groups, but the correlation for neuronal activation between these regions, as assessed with Fisher’s z-tests, is significantly different in proestrous females compared to other hormonal conditions (Bangasser et al. 2015). Asterisks indicate a significant difference (p < .05).