Sex differences in stress regulation of arousal and cognition

Abstract

There are sex differences in the prevalence and presentation of many psychiatric disorders. For example, posttraumatic stress disorder (PTSD) and major depression are more common in women than men, and women with these disorders present with more hyperarousal symptoms than men. In contrast, attention deficit hyperactivity disorder (ADHD) and schizophrenia are more common in men than women, and men with these disorders have increased cognitive deficits compared to women. A shared feature of the aforementioned psychiatric disorders is the contribution of stressful events to their onset and/or severity. Here we propose that sex differences in stress responses bias females towards hyperarousal and males towards cognitive deficits. Evidence from clinical and preclinical studies is detailed. We also describe underlying neurobiological mechanisms. For example, sex differences in stress receptor signaling and trafficking in the locus coeruleus-arousal center are detailed. In learning circuits, evidence for sex differences in dendritic morphology is provided. Finally, we describe how evaluating sex-specific mechanisms for responding to stress in female and male rodents can lead to better treatments for stress-related psychiatric disorders.

Keywords: Attention; Corticotropin releasing factor; Estrogen; Glucocorticoids; Memory; Norepinephrine.

Figure 1.

Schematics depict a sex difference in LC dendrites and how this could affect the processing of inputs. Dendrites of female LC neurons (A) are longer and more complex than dendrites of male LC neurons (B), which would increase the input from regions that project to the dorsolateral (green) and ventromedial (orange) peri-LC regions in females compared to males. Bar., Barrington’s nucleus; BNST, bed nucleus of the stria terminalis; CeA, central amygdala; NTS, solitary nucleus; PAG, periaqueductal gray; PGi, nucleus paragigantocellularis; PVN, paraventricular nucleus

Figure 2.

Images illustrate sex differences in CRF₁ receptors. In females, CRF₁ receptors bind to Gs and CRF₁ receptors do not internalize following stress and CRF overexpression, which leads to a large response to CRF (A). In males, CRF₁ receptors associate with βarrestin2 (βarr) and CRF₁ receptors internalize following stress and CRF overexpression, which results in a smaller response to CRF (B).

Figure 3.

Ovarian hormones regulate the effect of CRF on sustained attention. (A) The vigilance index, an overall measure of attentional performance, is disrupted by CRF (0.5 µg, i.c.v.) in male and diestrous female rats, but not in proestrous/estrous females. Reproduced with permission [165]. (B) Sustained attention circuitry comprised of the nucleus basalis of Meynert (NBM) and infralimibic cortex (IL) is activated by CRF in all groups, but the correlation for neuronal activation between these regions, as assessed with Fisher’s z-tests, is significantly different in proestrous female rats compared to males and diestrous females (Bangasser et al., 2015). *p < 0.05. Reproduced with permission [33].