The role of corticotropin-releasing factor in mediating the effect of acute stress on effort-based decision-making

The acute stress response is an adaptive response to threats in the environment, activating numerous coordinating systems to return the organism to homeostasis. Episodes of acute stress can have differential impacts on learning and memory functioning depending on myriad factors including the context, duration or timing of the stress. The manner in which acute stress influences higher-level cognitive function, including decision-making, however, is relatively less known. Decision-making involves weighing the alternative costs and benefits in order to optimize choice behavior. Increasing the amount of effort required in order to obtain a reward is one type of cost that can alter the subjective value of objectively larger rewards. Using an operant chamber assay, rats were required to choose between a low effort/low reward lever (LR; 2 pellets), and a high effort/high reward lever (HR; 4 pellets), with the effort requirement increasing over trial blocks (2, 5, 10, and 20 presses). Normally rats will choose the HR lever more often when the effort cost is low, reducing their preference for this option as the amount of effort increases. Previous research in our lab revealed that one hour of restraint stress reduces choice of the HR option in this task, which was not mimicked by systemic corticosterone (CORT) injection and not blocked by the dopamine (DA) antagonist, flupenthixol (Shafei et al.2012). The goal of the current study is to elucidate the neurochemical mechanisms underlying the ability of acute stress to reorganize effort-related decision-making preferences and to clarify the regional specificity of this action. Initial experiments found that corticotropin-releasing factor (CRF), which initiates the hypothalamic-pituitary-adrenal (HPA) axis, is primarily involved in mediating the effect of acute stress, as prior CRF antagonism (alpha-helical CRF; 30 μg) ameliorated the effect of one hour of acute restraint stress and central CRF infusion (3 μg) mimicked the effect of acute restraint stress on HR preference. The effect of CRF was not due to altering the subjective value of objectively larger rewards, as prior CRF administration (3 μg) had no effect on choice behavior when there were no costs associated with reward, however, this manipulation did reduce the motivation to work for reward, indicating that CRF acts in the effort-based decision-making task by reducing the drive to work for reward. Subsequent experiments aimed to investigate the regional specificity of CRF action in reorganizing effort-related preference behavior. With this in mind, we targeted the ventral tegmental area (VTA), as previous experiments revealed that CRF is released in the VTA in response to stress (Wang et al.,2005), and intra-VTA CRF reduces motivation to work for reward (Wanat et al.,2013). Intra-VTA, but not intra-nucleus accumbens (NAc) core, CRF infusion (0.5 μg) mimicked the effect of central CRF and acute restraint stress on HR preference, signifying the importance of this region in mediating the behavioral effect of acute stress on effort choice. Taken together, these experiments highlight the importance of CRF in mediating the effect of effort-based decision-making and indicate that CRF transmission may influence the motivational impairments and abnormal decision-making associated with human depression.Arts, Faculty ofPsychology, Department ofGraduat