Single Prolonged Stress as a Prospective Model for Posttraumatic Stress Disorder in Females

Abstract

Sex plays an important role in susceptibility to stress triggered disorders. Posttraumatic Stress disorder (PTSD), a debilitating psychiatric disorder developed after exposure to a traumatic event, is two times more prevalent in women than men. However, the vast majority of animal models of PTSD, including single prolonged stress (SPS), were performed mostly with males. Here, we evaluated SPS as an appropriate PTSD model for females in terms of anxiety, depressive symptoms and changes in gene expression in the noradrenergic system in the brain. In addition, we examined intranasal neuropeptide Y (NPY) as a possible treatment in females. Female rats were subjected to SPS and given either intranasal NPY or vehicle in two separate experiments. In the first experiment, stressed females were compared to unstressed controls on forced swim test (FST) and for levels of expression of several genes in the locus coeruleus (LC) 12 days after SPS exposure. Using a separate cohort of animals, experiment two examined stressed females and unstressed controls on the elevated plus maze (EPM) and LC gene expression 7 days after SPS stressors. SPS led to increased anxiety-like behavior on EPM and depressive-like behavior on FST. Following FST, the rats displayed elevated tyrosine hydroxylase (TH), CRHR1 and Y1R mRNA levels in the LC, consistent with increased activation of the noradrenergic system. The expression level of these mRNAs was unchanged following EPM, except Y1R. Intranasal NPY at the doses shown to be effective in males, did not prevent development of depressive or anxiety-like behavior or molecular changes in the LC. The results indicate that while SPS could be an appropriate PTSD model for females, sex differences, such as response to NPY, are important to consider.

Sex Differences in the Neuropeptide Y System and Implications for Stress Related Disorders

“…Male-specific changes within the Y2R system are also seen after exposure to stress. We observed a decrease in Y2R gene expression levels in the locus coeruleus after single prolonged stress as compared to unstressed controls only in males [ 56 , 136 , 137 ]. A decrease in Y2R expression would allow for more NPY and other neurotransmitters to be released into the synapse.…”

“…Alternatively, less Y1R could contribute to susceptibility to the effects of stress in females. We found that mRNA levels of Y1R and CRH receptor subtype 1 (CRHR1) in the locus coeruleus increased in female rats when examined 1 week or more after exposure to single prolonged stress as compared to unstressed controls [ 136 ]. The increase in gene expression could be a way to respond to stress and, in the case of Y1R, ameliorate the downstream effects of CRHR1.…”

“…At the same doses effective in males, intranasal NPY did not prevent the development of depressive-like or anxiety behavior after exposure of females to stress. Similarly, stress-elicited molecular changes in the locus coeruleus were not altered [136]. Interestingly, a recent clinical trial tested the effects of intranasal NPY in a cohort of patients with PTSD.…”

Systematic Review and Methodological Considerations for the Use of Single Prolonged Stress and Fear Extinction Retention in Rodents

“…For example, in an identical number of studies utilizing predator cues to model features of PTSD, of those that reported the biological sex of the animals, 97% used only male rats (3% not specified). Preliminary studies have documented sex-specificity in behavioral and neurological outcomes following SPS, e.g., females do not consistently exhibit the effects of SPS on extinction retention (Keller et al, 2015b;Ornelas and Keele, 2018;Pooley et al, 2018a,b;Nahvi et al, 2019;Nwokafor et al, 2020). However, females are equally sensitive to SPS effects on depressive-like behavior, increased anxiety, and elevated hippocampal glucocorticoid receptor expression (Keller et al, 2015a;Nahvi et al, 2019).…”

“…Preliminary studies have documented sex-specificity in behavioral and neurological outcomes following SPS, e.g., females do not consistently exhibit the effects of SPS on extinction retention (Keller et al, 2015b;Ornelas and Keele, 2018;Pooley et al, 2018a,b;Nahvi et al, 2019;Nwokafor et al, 2020). However, females are equally sensitive to SPS effects on depressive-like behavior, increased anxiety, and elevated hippocampal glucocorticoid receptor expression (Keller et al, 2015a;Nahvi et al, 2019). Additional efforts are underway to expand the application of SPS to female rats, in response to sex-specific biological findings and initiatives by primary funding agencies (reviewed in Clayton, 2018).…”