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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Linked Research project Grant (RL1)
Project #
5RL1DA024855-05
Application #
8111185
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Volman, Susan
Project Start
2007-09-30
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$233,866
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kim, Soyoun; Bobeica, Irina; Gamo, Nao J et al. (2012) Effects of ýý-2A adrenergic receptor agonist on time and risk preference in primates. Psychopharmacology (Berl) 219:363-75
Seo, Hyojung; Lee, Daeyeol (2012) Neural basis of learning and preference during social decision-making. Curr Opin Neurobiol 22:990-5
Lee, Daeyeol; Seo, Hyojung; Jung, Min Whan (2012) Neural basis of reinforcement learning and decision making. Annu Rev Neurosci 35:287-308
Kim, Soyoun; Lee, Daeyeol (2011) Prefrontal cortex and impulsive decision making. Biol Psychiatry 69:1140-6
Cai, Xinying; Kim, Soyoun; Lee, Daeyeol (2011) Heterogeneous coding of temporally discounted values in the dorsal and ventral striatum during intertemporal choice. Neuron 69:170-82
Curtis, Clayton E; Lee, Daeyeol (2010) Beyond working memory: the role of persistent activity in decision making. Trends Cogn Sci 14:216-22
Sul, Jung Hoon; Kim, Hoseok; Huh, Namjung et al. (2010) Distinct roles of rodent orbitofrontal and medial prefrontal cortex in decision making. Neuron 66:449-60
Hwang, Jaewon; Kim, Soyoun; Lee, Daeyeol (2009) Temporal discounting and inter-temporal choice in rhesus monkeys. Front Behav Neurosci 3:9
Kim, Soyoun; Hwang, Jaewon; Seo, Hyojung et al. (2009) Valuation of uncertain and delayed rewards in primate prefrontal cortex. Neural Netw 22:294-304
Lee, Daeyeol (2008) Game theory and neural basis of social decision making. Nat Neurosci 11:404-9