Sex differences in synaptic plasticity in stress-responsive brain regions following chronic variable stress

Increased stress responsiveness is implicated in the etiology of mood and anxiety disorders, including depression and post-traumatic stress disorder. Additionally, stress-related affective disorders have a higher incidence in women than men. Chronic stress in rodents produces numerous neuromorphological changes in a variety of limbic brain regions. Here, we examined the sex-dependent differences in presynaptic innervation of the paraventricular nucleus of the hypothalamus (PVN), prefrontal cortex (PFC), bed nucleus of the stria terminalis (BST), and amygdala in response to chronic variable stress (CVS). Following 14 days of CVS, the presynaptic protein synaptophysin was assessed in male and female rats. Our results demonstrate that synaptophysin staining density was higher in females than males in all brain areas evaluated, indicating sex differences in the organization of presynaptic innervation. After CVS, the PVN, principal nucleus of the BST (BSTpr), and basolateral nucleus of the amygdala (BLA) displayed significantly reduced synaptophysin density in females but not males. Furthermore, males showed an increase in synaptophysin in the PVN after CVS, suggesting a sex difference in the modulation of presynaptic inputs to the PVN following chronic stress. Overall, these data suggest marked sex differences in PVN, BSTpr, and BLA presynaptic innervation as a consequence of chronic stress, which may be associated with differential stress responsivity and perhaps susceptibility to pathologies in males and females.