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, underscoring the importance of stress history and coping strategy in determining the impact of stress. Finally, adolescent social stress produced an enduring impairment of cognitive flexibility that was seen in adulthood and occurred selectively in rats that resisted social defeat, further reinforcing the importance of coping style in the consequences of stress. Together these studies demonstrate how CRF modulation of monoamine systems can affect cognitive flexibility in ways that are adaptive for dealing with acute stress. They also show the importance of stress history, coping style, and age at which stress occurs as determinants of the impact of stress on cognition. This research may lead to the development of novel, individualized monoamine-targeted treatments for individuals suffering from stress-related cognitive impairments that may be related to the etiology of a diverse range of psychiatric disorders