Female HPA axis displays heightened sensitivity to pre-pubertal stress

Early life stress (ELS) is a risk factor in the development of psychiatric disorders. The underlying biological mechanisms governing this phenomenon are not fully understood, but dysregulation of stress responses is likely to play a key role. Males and females differ in their propensity to develop psychiatric disorders, with far higher rates of anxiety, major depressive disorder, affective disorders and post-traumatic stress disorder found in women. We hypothesized that sex differences in response to ELS may play a crucial role in differential vulnerability between the sexes. To test this, we evaluated the consequences of pre-pubertal stress (PPS) on the HPA axis in adult female and male Lister Hooded rats. PPS animals were exposed to swim, restraint and elevated platform stress on postnatal days 25-27, controls remained in their home cage. Once adult, animals were either a) sacrificed directly and brains collected or b) sacrificed 20 minutes or 1 week after a social test and trunk blood collected. In the female hippocampal formation, PPS increased expression of FKBP5 and AVPR1a. In the female prefrontal cortex, PPS resulted in increased glucocorticoid receptor expression, increased glucocorticoid:mineralocorticoid (GR:MR) receptor expression ratio and decreased AVPR1a expression. Females exposed to PPS did not show the normal rise in blood corticosterone levels following a social interaction test. In contrast, PPS did not alter the expression of oxytocin or oxytocin receptors, and no effects of PPS were seen in males. However, striking sex differences were found. Females had higher oxytocin receptor expression in the prefrontal cortex and AVPR1a and oxytocin expression in the hypothalamus, whereas males demonstrated higher expression of GR, MR, GR:MR, FKBP5 and oxytocin receptor in the hypothalamus. These results demonstrate heightened reactivity of the female HPA axis to PPS and may help explain why in humans females display an increased susceptibility to certain stress-related psychopathologies.LAY SUMMARYWomen are at greater risk of developing several psychiatric illnesses. Using a rodent model, we show that the female stress system is more reactive to the lasting effects of early life stress. This heightened reactivity of the female stress response may help explain why women are at a greater risk of developing psychiatric disorders.