Extinction is thought to be deficient in anxiety disorders such as PTSD, and there is a pressing need to translate animal findings in this area to humans. This five-year project represents the continuation of a close collaboration between two sites, one investigating fear extinction in rats (PI: Quirk, Univ. Puerto Rico), and the other in humans (Co-PI: Pitman, MGH-Harvard). Our main goal is to identify homologous structures in the rat and human prefrontal cortex that regulate fear and predict extinction, and to investigate these areas in PTSD. The prelimbic and infralimbic areas in rat prefrontal cortex impair and facilitate recall of extinction, respectively. In the human, the dACC and vmPFC serve similar functions to rat PL and IL, respectively. Our overarching hypothesis is that an imbalance in the activity of these prefrontal areas leads to extinction failure and PTSD. We will investigate these areas in rats and humans in four Specific Aims: 1) To investigate the activity and functional connectivity of rat prelimbic and infralimbic cortex prior to and following extinction of fear conditioning (using multichannel unit recording), and to identify neurobiological markers of extinction failure;2.) To facilitate extinction recall in rats by manipulating this prefrontal network pharmacologically;3) To investigate human homologues dACC and vmPFC in the acquisition and extinction of conditioned fear, and to identify neurobiological markers for extinction failure within these brain regions using PET-FDG and fMRI imaging in healthy humans;4) To characterize the activity of the dACC and vmPFC in PTSD patients and to determine whether neurobiological markers for extinction failure are present in this disorder. We predict that the PL/IL ratio of resting activity in rats, or dACC/vmPFC ratio of resting activity in healthy humans, will be inversely correlated with extinction. In PTSD, we predict that the dACC/vmPFC ratio will be increased and will be correlated with extinction failure. Moreover, we predict hypoactive vmPFC and hyperactive dACC in PTSD patients during extinction retention tests. Exposure therapies that are commonly used to treat anxiety disorders are based on extinction. In addition to elucidating the pathophysiology of PTSD, identifying neurobiological markers of extinction failure could become a screening tool for persons at high risk of trauma exposure. Identifying neurobiological interventions that improve extinction retention could lead to novel treatments for anxiety disorders, mood disorders, and addictions.

Public Health Relevance

Approximately 13% of the adult population in the U.S. suffer from an anxiety disorder, in which it is difficult to control or extinguish fear responses. This proposal will translate findings on the brain mechanisms of extinction from rats to humans, using neuronal recording and functional brain imaging, in order to identify neurobiological markers of extinction success or failure. If successful, this approach could lead to a screening tool for identifying persons at high risk for developing an anxiety disorder and could augment existing extinction-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081975-04
Application #
8207263
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2009-01-16
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
4
Fiscal Year
2012
Total Cost
$639,618
Indirect Cost
$71,529
Name
University of Puerto Rico Med Sciences
Department
Psychiatry
Type
Schools of Medicine
DUNS #
948108063
City
San Juan
State
PR
Country
United States
Zip Code
00936
Rosas-Vidal, Luis E; Do-Monte, Fabricio H; Sotres-Bayon, Francisco et al. (2014) Hippocampal--prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology 39:2161-9
Pendyam, Sandeep; Bravo-Rivera, Christian; Burgos-Robles, Anthony et al. (2013) Fear signaling in the prelimbic-amygdala circuit: a computational modeling and recording study. J Neurophysiol 110:844-61
Burgos-Robles, Anthony; Bravo-Rivera, Hector; Quirk, Gregory J (2013) Prelimbic and infralimbic neurons signal distinct aspects of appetitive instrumental behavior. PLoS One 8:e57575
Linnman, Clas; Zeidan, Mohamed A; Pitman, Roger K et al. (2012) Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning. Biol Psychol 89:450-9
Milad, Mohammed R; Quirk, Gregory J (2012) Fear extinction as a model for translational neuroscience: ten years of progress. Annu Rev Psychol 63:129-51
Zeidan, Mohamed A; Lebron-Milad, Kelimer; Thompson-Hollands, Johanna et al. (2012) Test-retest reliability during fear acquisition and fear extinction in humans. CNS Neurosci Ther 18:313-7
Linnman, Clas; Zeidan, Mohamed A; Furtak, Sharon C et al. (2012) Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit. Am J Psychiatry 169:415-23
Padilla-Coreano, Nancy; Do-Monte, Fabricio H; Quirk, Gregory J (2012) A time-dependent role of midline thalamic nuclei in the retrieval of fear memory. Neuropharmacology 62:457-63
Milad, Mohammed R; Rauch, Scott L (2012) Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 16:43-51
Sierra-Mercado, Demetrio; Padilla-Coreano, Nancy; Quirk, Gregory J (2011) Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology 36:529-38

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