Diurnal Fluctuations in HPA and Neuropeptide Y-ergic Systems Underlie Differences in Vulnerability to Traumatic Stress Responses at Different Zeitgeber Times

Abstract

The hypothalamic-pituitary-adrenal (HPA) axis displays a characteristic circadian pattern of corticosterone release, with higher levels at the onset of the active phase and lower levels at the onset of the inactive phase. As corticosterone levels modify the response to stress and influence the susceptibility to and/or severity of stress-related sequelae, we examined the effects of an acute psychological trauma applied at different zeitgeber times (ZTs) on behavioral stress responses. Rats were exposed to stress either at the onset of the inactive-(light) phase (ZT=0) or at the onset of the active-(dark) phase (ZT=12). Their behavior in the elevated plus-maze and acoustic startle response paradigms were assessed 7 days post exposure for retrospective classification into behavioral response groups. Serum corticosterone levels and the dexamethasone suppression test were used to assess the stress response and feedback inhibition of the HPA axis. Immunoreactivity for neuropeptide Y (NPY) and NPY-Y1 receptor (Y1R) in the paraventricular (PVN) and arcuate (ARC) hypothalamic nuclei, hippocampus, and basolateral amygdala were measured. The behavioral effects of NPY/Y1R antagonist microinfused into the PVN 30 min before stress exposure during the inactive or active phase, respectively, were evaluated. PVN immunoreactivity for NPY and Y1R was measured 1 day after the behavioral tests. The time of day of the traumatic exposure markedly affected the pattern of the behavioral stress response and the prevalence of rats showing an extreme behavioral response. Rats exposed to the stressor at the onset of their inactive phase displayed a more traumatic behavioral response, faster post-exposure corticosterone decay, and a more pronounced stress-induced decline in NPY and Y1R expression in the PVN and arcuate hypothalamic nuclei. Blocking PVN Y1R before stress applied in the active phase, or administering NPY to the PVN before stress applied in the inactive phase, had a resounding behavioral effect. The time at which stress occurred significantly affected the behavioral stress response. Diurnal variations in HPA and NPY/Y1R significantly affect the behavioral response, conferring more resilience at the onset of the active phase and more vulnerability at the onset of the inactive phase, implying that NPY has a significant role in conferring resilience to stress-related psychopathology.

Stress-induced neuroinflammatory priming is time of day dependent

“…However, the stressors used in these studies were milder than that used here. A recent study using inescapable predator scent also found that the glucocorticoid concentrations following a stressor were similar at different circadian phases (Cohen et al, 2015). Again, it is important to note that since basal corticosterone concentrations were lower in the light phase than in the dark phase, the increase from baseline produced by IS was greater in the light phase.…”

“…Rats exposed to a stressor at the onset of their inactive phase displayed increased anxiety-like behaviors in the elevated plus maze and acoustic startle response tests, compared to rats exposed to the same stressor during their active phase (Cohen et al, 2015). These behavioral differences are associated with differential regulation of NPY and Yr1 in the hypothalamus.…”

“…Interestingly, nocturnal rodents are more susceptible to the effects of stress during the light (inactive) phase as compared to the dark phase (Cohen et al, 2015). Rats exposed to a stressor at the onset of their inactive phase displayed increased anxiety-like behaviors in the elevated plus maze and acoustic startle response tests, compared to rats exposed to the same stressor during their active phase (Cohen et al, 2015).…”

“…However, whether diurnal timing of the stressor affects neuroinflammatory priming has not been established. Responses to stressors and susceptibility to and/or severity of stress-related comorbidities are regulated by the circadian system (Cohen et al, 2015). This suggests that microglia may also be differentially sensitive to the effects of stressors throughout the day.…”

The Role of Neuropeptide Y mRNA Expression Level in Distinguishing Different Types of Depression

“…Previous studies demonstrated that enhancing NPY function boosts resilience (Christiansen et al, 2011; Southwick and Charney, 2012; Cohen et al, 2015). NPY can be served as a potential anti-depressive factor and used to monitor treatment of depression by recent findings (Bigio et al, 2016; Nakhate et al, 2016; Ozsoy et al, 2016; Wagner et al, 2016).…”