Abstract
Early-life trauma can increase the risk for, and severity of, several psychiatric illnesses. These include drug use disorders, and some correlations appear to be stronger in women. Understanding the long-term consequences of developmental stressor or stress hormone exposure and possible sex differences is critically important. So-called “reversal learning” tasks are commonly used in rodents to model cognitive deficits in stress- and addiction-related illnesses in humans. Here, we exposed mice to the primary stress hormone corticosterone (CORT) during early adolescence (postnatal days 31–42), then tested behavioral flexibility in adulthood using an instrumental reversal learning task. CORT-exposed female, but not male, mice developed perseverative errors. Despite resilience to subchronic CORT exposure, males developed reversal performance impairments following exposure to physical stressors. Administration of a putative tyrosine kinase receptor B (trkB) agonist, 7,8-dihydroxyflavone (7,8-DHF), during adolescence blocked CORT-induced errors in females and improved performance in males. Conversely, blockade of trkB by ANA-12 impaired performance. These data suggest that trkB-based interventions could have certain protective benefits in the context of early-life stressor exposure. We consider the implications of our findings in an extended “Discussion” section.
Highlights
Reversal tasks assess the ability of mice or rats to flexibly modify behaviors when reinforcement contingencies change
In a population of predominantly male treatment-seeking individuals with alcohol dependence, lateral oPFC (loPFC) surface area and volume were smaller in individuals who subsequently relapsed in a 1-year period compared to individuals who remained abstinent (Cardenas et al, 2011; Durazzo et al, 2011). These findings suggest that prefrontal cortex (PFC) subregions disrupted by both adolescent stress or glucocorticoid exposure and drugs of abuse may be sex-dependent
Being able to implement new strategies to promote behavioral change and control impulsive responses may be critical to treatment response—among cocaine-dependent individuals undergoing cognitive-behavioral therapy, higher impulsivity/risk-taking before treatment is associated with poorer treatment retention and higher relapse rates (Carroll et al, 2011)
Summary
Reversal tasks assess the ability of mice or rats to flexibly modify behaviors when reinforcement contingencies change These tasks are commonly used to model behavioral inflexibility associated with addiction and other disorders in humans (for recent review Izquierdo et al, 2017). Animals are trained to associate specific actions or stimuli with reward (e.g., food), the association is modified such that a previously non-predictive contingency could be used to obtain reinforcement, while the original contingency is no longer predictive. These tasks require animals to inhibit a familiar response strategy and deploy a new strategy to obtain reinforcement.
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