Patients with lesions in the orbitofrontal cortex display characteristic behavioral deficits in various decision- making tasks. They are impaired in revising their behavioral strategies when the previously advantageous actions no longer produce desirable outcomes and integrating multiple dimensions of the decision outcomes to make optimal choices. These behavioral changes resemble the symptoms of drug addicts who are unable to discontinue the use of abused substance that are no longer pleasurable and lead to negative consequences. Dysfunctions of the orbitofrontal cortex are also implicated in many mood and anxiety disorders. In addition, patients with orbitofrontal lesions are unable to take into consideration hypothetical outcomes from unchosen actions to improve their decision-making strategies. Despite this wide clinical implication of the orbitofrontal dysfunctions, the nature of specific computational steps embodied in the orbitofrontal cortex and disrupted in many mental disorders is unknown. Studies proposed in this application will investigate how multiple reward- related parameters and various decision variables are encoded and integrated by individual neurons of the primate orbitofrontal cortex. First, we will test whether the neurons in the orbitofrontal cortex will integrate multiple reward parameters during an inter-temporal gambling task in which the magnitude, delay, and uncertainty of reward available from each option is systematically manipulated. Second, we will investigate whether neurons in different subdivisions of the orbitofrontal cortex tend to specialize in propagating the signals related to positive and negative outcomes. This will be tested in a token-based decision-making task in which the animal's choice behaviors are reinforced and punished by the delivery and removal of conditioned reinforcers, respectively. Finally, we will also test whether the information about the hypothetical outcomes from unchosen actions are reflected and integrated with the signals related to the animal's choices in the activity of orbitofrontal neurons. The results from these experiments will elucidate how the signals originating from different sources are integrated and transformed in the orbitofrontal cortex so that they can be used directly to guide the animal's choices. Accordingly, the proposed studies will contribute to prevention and more efficient treatment strategies for substance abuse and other mental disorders that involve the orbitofrontal cortex.

Public Health Relevance

Lesions and abnormal activity in the orbitofrontal cortex produces a variety of behavioral impairments, often highlighted by the failures in adaptively learning the optimal decision-making strategies. Accordingly, orbitofrontal dysfunctions are implicated in drug addiction and other psychiatric disorders, including anxiety and mood disorders. Combining a series of novel behavioral tasks and multi-channel neurophysiological recordings, the proposed studies will elucidate the cellular basis for information processing in the orbitofrontal cortex and contribute to improving diagnosis and treatment strategies for many mental illnesses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA029330-01
Application #
7902755
Study Section
Special Emphasis Panel (ZRG1-IFCN-L (02))
Program Officer
Volman, Susan
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
1
Fiscal Year
2010
Total Cost
$372,375
Indirect Cost
Name
Yale University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Constantinidis, Christos; Funahashi, Shintaro; Lee, Daeyeol et al. (2018) Persistent Spiking Activity Underlies Working Memory. J Neurosci 38:7020-7028
Massi, Bart; Donahue, Christopher H; Lee, Daeyeol (2018) Volatility Facilitates Value Updating in the Prefrontal Cortex. Neuron 99:598-608.e4
Farashahi, Shiva; Donahue, Christopher H; Khorsand, Peyman et al. (2017) Metaplasticity as a Neural Substrate for Adaptive Learning and Choice under Uncertainty. Neuron 94:401-414.e6
Kleinman, Matthew R; Sohn, Hansem; Lee, Daeyeol (2016) A two-stage model of concurrent interval timing in monkeys. J Neurophysiol 116:1068-81
Lee, Daeyeol; Seo, Hyojung (2016) Neural Basis of Strategic Decision Making. Trends Neurosci 39:40-48
Kim, Ko-Un; Huh, Namjung; Jang, Yunsil et al. (2015) Effects of fictive reward on rat's choice behavior. Sci Rep 5:8040
Seo, Hyojung; Cai, Xinying; Donahue, Christopher H et al. (2014) Neural correlates of strategic reasoning during competitive games. Science 346:340-3
Livingstone, Margaret S; Pettine, Warren W; Srihasam, Krishna et al. (2014) Symbol addition by monkeys provides evidence for normalized quantity coding. Proc Natl Acad Sci U S A 111:6822-7
Murray, John D; Bernacchia, Alberto; Freedman, David J et al. (2014) A hierarchy of intrinsic timescales across primate cortex. Nat Neurosci 17:1661-3
Jo, Suhyun; Kim, Ko-Un; Lee, Daeyeol et al. (2013) Effect of orbitofrontal cortex lesions on temporal discounting in rats. Behav Brain Res 245:22-8

Showing the most recent 10 out of 18 publications