Modeling stress pathway dysregulation in affective disorders

Stress experience is a common precipitating factor in affective disorder onset, yet the neurobiological mechanisms that underlie adaptive and maladaptive stress responses remain unknown. To elucidate how stress sensitivity and aberrant function of the primary stress neuropeptide corticotropin-releasing factor (CRF) may induce disease predisposition, we examined electrophysiological effects of CRF on the serotonin (5-HT) producing raphe nuclei and studied the molecular and behavioral effects of chronic, mild stress exposure on gene expression related to CRF and 5-HT. In addition to CRF inducing significant changes in 5-HT cell physiology, we also observed that stress increased expression of the rate limiting synthesis enzyme for 5-HT and of CRF receptor-1, produced increased behavioral arousal, and widespread upregulation of anti-apoptotic gene expression in the raphe. In contrast, the stress-sensitive mouse model deficient in CRF receptor-2 (R2KO) displayed increased cellular excitability at rest, and systematically failed to display stress-mediated changes. These mice also exhibited significant cell death and elevated apoptotic signaling in the raphe following stress supporting the maladaptive nature of the R2KO stress response. The connection between stress sensitivity and 5-HT function was further supported by findings that acute challenge with the 5-HT reuptake inhibitor citalopram produced increased sensitivity in behavioral and physiological stress tests among stress-sensitive groups, including R2KO mice and females. We found evidence suggesting that these effects may be regulated by upstream differences in CRF-producing brain regions such as the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala (CeA), which in females and R2KO mice displayed basal differences related to epigenetic regulation of CRF and excitatory drive. These stress-sensitive groups also showed elevated neurobiological stress responses in the BNST and CeA, suggesting that CRF dysregulation and sex differences each confer unique susceptibility in key CRF-producing brain regions that may induce maladaptive changes in the 5-HT systems and promote a systemic dysregulation in the brain after chronic stress. Together, these results indicate that adaptive stress responses require a complex orchestration of regulation in the brain, and suggest that a failure to produce these changes may be a critical predictor of affective disorder susceptibility.