Stress can be defined as any real or perceived threat to the psychological and physical integrity of an individual, and despite its short-term adaptive value, can cause behavioral, emotional, cognitive, and immune changes in affected individuals that are potentially harmful. Furthermore, stress can indirectly lead to other negative health consequences by altering the behavioral strategies of the individuals. For example, it has been demonstrated that stress can lead to poor diet, obesity, and substance abuse. It has been hypothesized that such maladaptive behaviors might arise as a result of stress-induced weakening of the prefrontal cortical functions. Previous studies of stress-induced changes in prefrontal functions showed that excessive dopamine and norepinephrine release in prefrontal cortex contributed to working memory impairment. However, the effects of stress on the decision-making functions of the prefrontal cortex have not been studied. In particular, impulsive choice is a strong predictor for many addictive behaviors, such as smoking and substance abuse, that are exacerbated by stress. Therefore, the effect of stress on impulsivity and prefrontal functions will be the focus of this project. In the proposed study, impulsivity will be quantified by the animal's tendency to choose a small but immediate reward rather than a large but delayed reward in an inter-temporal choice task. First, it will be tested whether impulsivity is increased by a pharmacological stressor, FG7142. Second, the role of dopaminergic and/or noradrenergic pathways in the regulation of impulsive choice behavior will be tested using receptor specific agonists and antagonists. Third, we will examine how these pharmacological manipulations affect the neural process of discounting the value of delayed reward by recording the single-neuron activity of neuronal ensembles in the prefrontal cortex with and without the same pharmacological manipulations. Fourth, using the combination of iontophoresis and single-neuron recording, it will be tested whether prefrontal functions related to impulsive choice behaviors are altered by dopamine and norepinephrine through their direct actions on the prefrontal micro-circuitry. Overall, the results from these experiments will provide a critical piece of information regarding the cellular basis of stress-mediated impairments in adaptive behavioral strategies and normal prefrontal functions, and thereby contribute to the development of new preventive and therapeutic measures against stress-mediated disease processes.
