- The 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. Since 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 (ZT) 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 seven 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 were measured one 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 prior to stress applied in the active phase, or administering NPY to the PVN prior to 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 plays a significant role in conferring resilience to stress-related psychopathology.Neuropsychopharmacology accepted article preview online, 22 September 2014. doi:10.1038/npp.2014.257.