Stress, Monoamines, and Cognitive Flexibility

Stress has been implicated in psychiatric disorders that are characterized by impaired executive function, which is mediated by the prefrontal cortex (PFC). The stress-related neuropeptide, corticotropin-releasing factor (CRF) regulates monoamine systems that project to the PFC, including the locus coeruleus norepinephrine (LC-NE) system and the dorsal raphe-serotonin (DRN-5-HT) system. CRF actions on these systems may underlie cognitive symptoms of stress-related disorders. The age at which stress occurs can determine its impact, and adolescent stress has been linked to adult psychopathology. This dissertation explores the role of CRF in stress-induced modulation of the LC-NE and DRN-5-HT systems and the developmental time course of the impact of stress on PFC-dependent cognitive function using attentional set-shifting tasks, microdialysis, and immunohistochemistry. CRF microinfusion into the LC and DRN produced dose-dependent effects on distinct cognitive functions. Low doses CRF in the LC facilitated set-shifting and increased c-fos expression in the PFC. In contrast, high doses of CRF in the LC facilitated reversal learning, suggesting that mild and severe stress affect different cognitive processes through LC-PFC projections. In the DRN, CRF facilitated set-shifting at a dosage that decreased 5-HT levels in the PFC. This effect switched to facilitation of reversal learning in a defeat-resistant subpopulation of rats exposed to social stress, underscorin