A fundamental problem in the neurobiology of learning and memory is understanding the neural mechanisms of extinction. Behavior acquired as the result of Pavlovian conditioning can be extinguished by presenting the conditioned stimulus (CS) repeatedly without the unconditioned stimulus (US); this is known as the extinction effect. Although many neural activity studies of extinction imply that extinction is the reversal of acquisition, the behavioral phenomena of spontaneous recovery and disinhibition suggest that this is not the case and that extinction does not result in the loss or unlearning of the CS- US association in the brain. The behavioral training paradigm of Pavlovian conditioned suppression (conditioned emotional response, or CER procedure) will be used in all the proposed studies. The brain metabolic effects of extinction will be assessed with uptake of fluorodeoxyglucose (FDG). Metabolic responses from experimental rats will be compared to those of control rats exposed to the same tone to identify which regional activity changes occur in response to the tone conditioned stimulus (CS) after extinction of the CER. In addition, we will examine which of these brain metabolic activity changes are correlated with variations in the behavioral performance of each subject.
The specific aims are to use the FDG brain mapping technique to test three hypotheses: 1) The hypothesis that extinction is the opposite of acquisition, which predicts that extinction involves the loss of unlearning of the CS-US associative effects on the brain; 2) The hypothesis that extinction is similar to long-term habituation, which suggests that CS salience of the tone will be modulated in auditory and arousal systems; and 3) Pavlov s hypothesis that extinction is a form of inhibition of the conditioned response. Specifically, it is predicted that the CER extinction effect is due to the inhibition of the neural representation of the CS-CER association in the prefrontal cortex and central amygdala. In contrast, reversals of learning effects on other neural circuits are expected to be minor during extinction due to the savings of CS-US associative effects unrelated to CER inhibition. In the CER paradigm, a better understanding of extinction mechanisms may also have important clinical implications, such as the therapeutic use of extinction to reduce undesired conditioned fears.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037755-02
Application #
2892433
Study Section
Special Emphasis Panel (ZRG2-BPO (01))
Program Officer
Nichols, Paul L
Project Start
1998-09-05
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Austin
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
City
Austin
State
TX
Country
United States
Zip Code
78712
Barrett, Douglas W; Gonzalez-Lima, F (2018) Prefrontal-limbic Functional Connectivity during Acquisition and Extinction of Conditioned Fear. Neuroscience 376:162-171
Bruchey, A K; Gonzalez-Lima, F (2008) Enhanced metabolic capacity of the frontal cerebral cortex after Pavlovian conditioning. Neuroscience 152:299-307
Puga, Frank; Barrett, Douglas W; Bastida, Christel C et al. (2007) Functional networks underlying latent inhibition learning in the mouse brain. Neuroimage 38:171-83
Wrubel, Kathryn M; Riha, Penny D; Maldonado, Monica A et al. (2007) The brain metabolic enhancer methylene blue improves discrimination learning in rats. Pharmacol Biochem Behav 86:712-7
Bruchey, A K; Shumake, J; Gonzalez-Lima, F (2007) Network model of fear extinction and renewal functional pathways. Neuroscience 145:423-37
Wrubel, Kathryn M; Barrett, Douglas; Shumake, Jason et al. (2007) Methylene blue facilitates the extinction of fear in an animal model of susceptibility to learned helplessness. Neurobiol Learn Mem 87:209-17
Zhang, Xian; Jones, Dirk; Gonzalez-Lima, F (2006) Neurodegeneration produced by rotenone in the mouse retina: a potential model to investigate environmental pesticide contributions to neurodegenerative diseases. J Toxicol Environ Health A 69:1681-97
Colorado, Rene A; Shumake, Jason; Conejo, Nelida M et al. (2006) Effects of maternal separation, early handling, and standard facility rearing on orienting and impulsive behavior of adolescent rats. Behav Processes 71:51-8
Zhang, Xian; Rojas, Julio C; Gonzalez-Lima, F (2006) Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res 9:47-57
Hu, Dan; Xu, Xiaojuan; Gonzalez-Lima, Francisco (2006) Vicarious trial-and-error behavior and hippocampal cytochrome oxidase activity during Y-maze discrimination learning in the rat. Int J Neurosci 116:265-80

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