Therapeutic effects of extinction learning as a model of exposure therapy in rats
Open accessAbstract
Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets.
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Chronic stress, such as chronic unpredictable stress and repeated restraint stress, produces a deficit in extradimensional set-shifting on the AST in rodents.
“chronic stress (for example, chronic unpredictable stress (CUS) and repeated restraint stress) has been shown to produce a deficit in ED set-shifting on the AST in rodents (Bondi et al 2008, Fucich et al 2016, Jett & Morilak 2013, Liston et al 2006, Morilak et al 2005)”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Fucich et al 2016
Fear extinction rescues a deficit in set-shifting caused by chronic stress.
“fear extinction rescues a deficit in set-shifting caused by chronic stress”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Fucich et al 2016
The effects of fear extinction on set-shifting are mediated by neuronal activation and de novo protein synthesis in the IL region of the mPFC.
“these effects are mediated by neuronal activation and de novo protein synthesis in the IL region of the mPFC (Fucich et al 2016).”
From Prefrontal cortex executive processes affected by stress in health and disease (2018) · cites this paper as Fucich et al 2016
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Prefrontal cortex executive processes affected by stress in health and disease
Girotti, M., Adler, S. M., Bulin, S. E., Fucich, E. A., Paredes, D., & Morilak, D. A. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.07.004 · Cited by 176 · see citing works
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- Authors
- Fucich, E. A., Paredes, D., & Morilak, D. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Morilak, David A
- Venue
- Neuropsychopharmacology
- Published
- 2016-07-15
- Volume
- 41
- Issue
- 13
- Pages
- 3092-3102
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC5101557
- OpenAlex
- W2468820376
- Cited by
- 24
- References
- 55
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 5 · 2017: 3
- FWCI
- 2.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX003512)
- William and Ella Owens Medical Research Foundation
- National Institutes of Health (UL1TR001120, TL1TR001119)
- National Institute of Mental Health (MH072672, R01MH072672)
- National Institute of Neurological Disorders and Stroke (T32NS082145)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- extinction learning, exposure therapy, chronic unpredictable mild stress, cognitive flexibility, coping styles, depression, post-traumatic stress disorder, fear conditioning, set-shifting, S6 phosphorylation, medial prefrontal cortex, anisomycin, stress-related psychiatric disorders
- MeSH terms
- Adaptation, Psychological, Animals, Anisomycin, Association Learning, Attention, Brain, Conditioning, Psychological, Cues, Disease Models, Animal, Electroshock, Extinction, Psychological, Fear, Implosive Therapy, Male, Protein Synthesis Inhibitors, Stress, Psychological, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Ribosomal Protein S6, Rats
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