Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Stress during childhood and adolescence enhances the risk of psychopathology later in life. In fact, exposure to stress during this period is known to predispose individuals to the development of psychopathologies such as depression and anxiety disorders later in life. Similarly, individuals subjected to fearful experiences or abuse during childhood and puberty exhibit violent behaviors in adulthood, as revealed in both human literature and animal studies. Previous work from our laboratory has shown that exposing peripuberty rats to fear experiences (such as synthetic fox odor and exposure to an elevated platform) following an unpredictable schedule, on a range of 7 specific days across P28 to P42 in male Wistar rats leads to reduced sociability, increased aggression, anxiety- and depression-like behaviors in adulthood. The hypothalamic pituitary adrenal (HPA) axis is one of the main physiological stress systems and various components of the HPA axis like corticotropin releasing hormone (CRH), glucocorticoids are modulated in response to early life experience. We therefore sought to investigate the role of HPA axis in long term programming of social and emotional behaviors as a result of peripuberty stress(PPS). We addressed this by manipulating (i) glucocorticoid system by two approaches, and, (ii) corticotropin releasing hormone (CRH) system. First, using male Wistar rats, we evaluated the consequences of administration of corticosterone following the same experimental schedule as for stress administration in our peripuberty stress paradigm (without actual stress exposure) on play behavior on postnatal day 44 (P44) and on behavioral tests of anxiety, aggression, sociability and depression in adulthood. Corticosterone response to novelty was also measured in adulthood. Our results show that, as compared to vehicle-, corticosterone-treated animals exhibit higher aggressive play behavior during adolescence, and escalated aggressive behavior in adulthood, while reduced sociability and decreased corticosterone response to novelty in adulthood. No differences were observed between groups on anxiety- and depression-like behavior tested later in life. Next, we examined whether pharmacological blockade of glucocorticoid receptor 30 minutes prior to peripuberty stress would prevent the consequences of peripuberty stress on emotional, social behavior and dysregulated gene expression. Our findings showed that administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty stress on behaviors related to the domain of aggression and sociability in adulthood without producing any effect on anxiety- and depression-like behavior tested later in life. Interestingly, administration of GR antagonist in PPS animals also reversed the effects of PPS on increased expression of GR and Trpc5 genes in central nucleus of amygdala. We also observed increased Crhr1 expression in limbic areas in peripuberty stressed animals which was not reversed by administration of GR antagonist in peripuberty stressed animals. Subsequently, we sought to evaluate the consequences of counteracting CRHR1 activation during early post-stress period on long-term behavioral consequences of peripuberty stress in tests for anxiety- and depression-like behaviors. Our results showed that administration of CRHR1 antagonist post peripuberty stress rescued the effects of peripuberty stress on depression-like behavior and to some extent on anxiety- like behavior. Taken together, our studies show that corticosterone administration during peripuberty largely mimics the behavioral alterations observed in peripuberty stressed animals in social realm, administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty on social domain and on increased expression of GR and Trpc5 genes in central nucleus of amygdala, and administration of CRHR1 antagonist post peripuberty stress rescued the effects of PPS on depression-like behavior and to some extent on anxiety-like behavior.