Sex differences in stress-related psychiatric disorders: neurobiological perspectives

Abstract

Stress is associated with the onset and severity of several psychiatric disorders that occur more frequently in women than men, including posttraumatic stress disorder (PTSD) and depression. Patients with these disorders present with dysregulation of several stress response systems, including the neuroendocrine response to stress, corticolimbic responses to negatively valenced stimuli, and hyperarousal. Thus, sex differences within their underlying circuitry may explain sex biases in disease prevalence. This review describes clinical studies that identify sex differences within the activity of these circuits, as well as preclinical studies that demonstrate cellular and molecular sex differences in stress responses systems. These studies reveal sex differences from the molecular to the systems level that increase endocrine, emotional, and arousal responses to stress in females. Exploring these sex differences is critical because this research can reveal the neurobiological underpinnings of vulnerability to stress-related psychiatric disorders and guide the development of novel pharmacotherapies.

Keywords: Arousal; Corticotropin releasing factor; Depression; Emotion; Hypothalamic pituitary adrenal axis; Locus coeruleus; Posttraumatic stress disorder; Sex difference; Stress.

Figure 1

Schematic representing the circuitry primarily responsible for mediating symptoms of PTSD and depression. The HPA axis that regulates the neuroendocrine responses to stress is shown in green. The corticolimbic circuitry that mediates emotional responses to negatively valenced stimuli is shown in red. The LC-norepinephrine system that initiates arousal responses to stress is shown in blue. AC: adrenal cortex; Amyg: amygdala; AP: anterior pituitary; HPC: hippocampus; LC: locus coeruleus; PFC: prefrontal cortex; PVN: paraventricular nucleus

Figure 2

Schematic representing sex differences in the HPA axis response to stress in rodents. Compared to male rats (left panel), female rats (right panel) have greater stress-induced release of CRF, ACTH, and corticosterone (cort.) due to sex differences in the hypothalamus, anterior pituitary (AP), and the cortex of the adrenal gland (AC). Negative feedback (shown with the red arrows) is also decreased in females is thought to be due to sex differences in GR expression, GR translocation, and GABAergic inhibition. Reduced negative feedback in females can further increase the release of stress hormones.

Figure 3

Schematic depicting sex differences in the LC–arousal system in rodents. The images on the left depict LC neurons with dendrites that are longer and more complex in females (bottom left panel) compared to males (top left panel). The longer dendrites of females are more likely to receive limbic afferents that terminate in peri-LC region. However, males and females would likely receive comparable amounts of input from autonomic regions that synapse near the cell bodies. The images on the right depict magnified views of LC dendrites to illustrate sex differences in the CRF₁ receptor coupling and trafficking. The top right panel shows how CRF₁ receptors (purple) of males associate with βarrestin2 (βarr.) and internalize following stressor exposure. In contrast, the bottom right panel shows how CRF₁ receptor of females couple to Gs and traffic to the plasma membrane following stressor exposure.