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. Here we review some of this recent literature using a framework developed by McCarthy and colleagues (2012) that highlights different types of sex differences. First, we detail how learned fear responses in rats are sexually dimorphic. Then we contrast this finding to 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 to better treat these disorders in both men and women.

Signatures of sex: Sex differences in gene expression in the vertebrate brain

“…Besides the reproductive organs, most sex differences in the body are quantitative, in which the distribution differs between the two sexes but largely overlaps, as is the case with height or brain volume (Maney, 2016;Ritchie et al, 2018), as well as many physiological traits such as stress (Bangasser & Wicks, 2017), opioid sensitivity (Averitt, Eidson, Doyle, & Murphy, 2019), and immune response (Klein & Flanagan, 2016). What can manifest as a sex difference in a specific behavior, neural response, or gene expression may in fact originate from underlying differences in physiology.…”

Acute stress induces long-lasting alterations in the dopaminergic system of female mice

“…However, there is limited knowledge of how stress affects the female brain, despite evidence that sex strongly influences an individual’s response to environmental challenges (Cahill, 2006; Gruene et al, 2015; Taylor et al, 2000; Trainor, 2011). Considering females exhibit higher sensitivity to stress (Carpenter et al, 2017; Dalla et al, 2005; Handa et al, 1994; Lin et al, 2008), a higher prevalence for mood disorders (Bale and Epperson, 2015; Bangasser and Valentino, 2014; Bangasser and Wicks, 2017; Kessler, 2003), and addiction-relevant behavior (Anker and Carroll, 2011; Calipari et al, 2017), it appears that this understudied population is particularly at risk for maladaptive, stress-induced physiological and behavioral alterations. Nonetheless, few studies have examined the basic characteristics of DA signaling in females, and even fewer have also examined its interaction with stress (Campi et al, 2014; Holly et al, 2012; Shimamoto et al, 2015; Trainor, 2011).…”

How does sex matter? Behavior, stress and animal models of neurobehavioral disorders

“…Unpredictability, novelty, lack of control, threat to self-esteem are reported as the key factors making people perceive a situation as stressful, and eliciting a physiological and psychological stress response. However, human and animal data clearly indicate that individuals' perception of the stressfulness of a situation as well as the physiological and behavioral responses to stress are strongly dependent on gender, and conditions that are stressful for males are not necessarily stressful for females, and the reverse (Palanza, 2001;Kudielka and Kirschbaum, 2005;Kokras and Dalla, 2014;Bangasser and Wicks, 2017).…”