Activation of the HPA-axis is among the first responses to cerebral ischemia, and glucocorticoid exposure prior to and following stroke is a critical determinant of ischemic outcome. Perinatal environment may be an important determinant of HPA-axis efficiency, influencing the onset of psychopathology and age-related disease. The present work examined the effects of brief (BMS) and extended (EMS) maternal separation, and prenatal stress (PNS), on stroke recovery in adult mice.
Despite improved HPA-axis responsivity to acute stressors, BMS male mice had significantly more ischemia-induced neuronal death and increased functional deficits following MCAO in adulthood. The increase in corticosterone-induced neuronal death, and increased inflammation, suggest that BMS mice are more sensitized to the detrimental effects of elevated corticosterone during ischemia. Female BMS mice exhibited similar exacerbation of stroke outcomes to the males when exposed to the MCAO model of focal ischemia, but not the CA/CPR model of global ischemia. EMS and PNS had minimal consequences on focal ischemic outcome in male and female mice. Though additional experiments are needed to determine mechanisms, these studies clearly demonstrate that neonatal environment can drastically affect adult sensitivity to ischemic injury by altering the HPA-axis and inflammatory responses.
Psychobiological determinants of stroke outcome are not limited, however, to manipulations of the early environment. Affiliative social interaction via pair-housing was determined to decrease infarct size, functional deficits, and inflammation in comparison to socially isolated mice. In addition, pair-housing reduced the negative consequences of BMS, with pair-housed BMS males exhibiting decreased infarct and functional deficits compared to socially isolated BMS males. In contrast to affiliative social behaviors, post-stroke depression impairs functional recovery and increases mortality following stroke. The final experiments investigated glucocorticoid- and interleukin-1-activity in post-stroke anhedonia. The data suggested that anhedonia is a valid index of post-stroke depressive-like behavior in mice, and can be effectively attenuated with IL-1ra.
Together, the experiments suggest that psychobiological processes that alter glucocorticoid exposure significantly influence neuronal survival and functional outcome following ischemia in adult mice. Indeed, perinatal determinants of HPA axis development, social modulation of stress responsivity, and post-stroke depression are important mediators of peri-ischemic glucocorticoid- and inflammatory cytokine exposure, significantly influencing physiological and behavioral outcomes.