Stress, glucocorticoid receptor and social behaviors

Abstract

Peripuberty, comprising childhood and adolescence, constitutes an important time window in the brain development and maturation. Exposure to prolonged stress during this period has been shown to increase the risk for the development of psychopathologies later in life. However, the mechanisms leading to the pathology are still poorly understood. Our laboratory has established a rat model of psychopathology based on unpredictable exposure to different stressors at peripuberty. Previous work on this model has revealed psychopathology-like behaviors in adult rats including pathological aggression and altered sociability. Interestingly, implication of the glucocorticoids, end product of the hypothalamic-pituitary-adrenal (HPA) axis, in the social deficits has been suggested. The glucocorticoids exert their functions through binding to two receptors, the mineralocorticoid (MR) and glucocorticoid receptor (GR). This thesis focused on the GR, as it is the major mediator of the neurobehavioral actions of stress, and its role in the programming and modulation of social behaviors. In the first study, we examined whether blocking glucocorticoid action prior to peripubertal stress (PPS) prevents the subsequent behavioral deficits. We observed that administration of a GR antagonist prior to each stress exposure reversed the alterations in social but not emotional domain at adulthood. Furthermore, the treatment normalized the increased expression of GR in the central amygdala (CeA) found in PPS rats. The CeA is strongly implicated in the regulation of social behaviors. Next, we evaluated the role of GR expression in this brain region in naive rats. We showed that viral downregulation of this receptor had an anxiolytic effect and reduced aggression. We then examined whether administration of the same treatment as described above also reverses PPS-induced behavioral dysfunctions when given at adulthood. Injections of the GR antagonist normalized the pathological aggression observed in adult PPS rats, but not the anxiety or sociability deficits. The third study focused on play fighting, a behavior essential for the development of social skills. We investigated the effects of PPS on play fighting at adolescence and analyzed the expression of genes related to the endocannabinoid, dopamine and opioid systems in the nucleus accumbens (NAc) and basolateral amygdala (BLA). These systems were reported as pivotal modulators of play fighting. We showed that PPS protocol led to enhanced play fighting, together with differential expression of the genes linked to endocannabinoid signaling in the NAc shell. The mitochondrial respiration in the amygdala was also increased in PPS animals following play fighting. Furthermore, play levels predicted some behavioral dysfunctions observed in adult PPS rats. Finally, we studied the role of GR expression in the NAc in the attainment of social rank. We showed that viral downregulation of GR in this nucleus had an anxiolytic effect and enhanced dominance. Rats infused with the virus also exhibited reduced mitochondrial respiration in the NAc. In summary, we have highlighted GR as an important modulator of social behaviors both under normal conditions and after exposure to peripubertal stress. Expression of this receptor in the CeA is tightly linked with aggressive phenotype, whereas in the NAc, GR expression plays a role in social dominance.