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Active Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions
Open accessAbstract
Signaled active avoidance (AA) paradigms train subjects to prevent an aversive outcome by performing a learned behavior during the presentation of a conditioned cue. This complex form of conditioning involves pavlovian and instrumental components, which produce competing behavioral responses that must be reconciled for the subject to successfully avoid an aversive stimulus. In signaled AA paradigm for rat, we tested the hypothesis that the instrumental component of AA training recruits infralimbic prefrontal cortex (ilPFC) to inhibit central amygdala (CeA)-mediated Pavlovian reactions. Pretraining lesions of ilPFC increased conditioned freezing while causing a corresponding decrease in avoidance; lesions of CeA produced opposite effects, reducing freezing and facilitating avoidance behavior. Pharmacological inactivation experiments demonstrated that ilPFC is relevant to both acquisition and expression phases of AA learning. Inactivation experiments also revealed that AA produces an ilPFC-mediated diminution of pavlovian reactions that extends beyond the training context, even when the conditioned stimulus is presented in an environment that does not allow the avoidance response. Finally, injection of a protein synthesis inhibitor into either ilPFC or CeA impaired or facilitated AA, respectively, showing that avoidance training produces two opposing memory traces in these regions. These data support a model in which AA learning recruits ilPFC to inhibit CeA-mediated defense behaviors, leading to a robust suppression of freezing that generalizes across environments. Thus, ilPFC functions as an inhibitory interface, allowing instrumental control over an aversive outcome to attenuate the expression of freezing and other reactions to conditioned threat.
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“Prior rodent research has demonstrated that behavioral control over an aversive stimulus reduces Pavlovian threat responses, even when control is no longer possible, and involves the vmPFC and striatum (Baratta et al., 2007; Cain and LeDoux, 2007; Moscarello and LeDoux, 2013; Ramirez et al., 2015).”
From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Moscarello and LeDoux, 2013
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“The vmPFC is proposed to toggle between these different output paths of the amygdala, shifting the flow of information to promote aversively motivated action instead of Pavlovian freezing responses (Moscarello and LeDoux, 2013; Ramirez et al., 2015).”
From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Moscarello and LeDoux, 2013
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“This indicates that plasticity in the IL is critical for the persistent reduction of conditioned responses with avoidance [112].”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [112]
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“One benefit of avoidance learning over extinction for controlling threat reactions is that avoidance learning results in a persistent reduction in the passive conditioned response, even when the avoidance action is no longer available [112].”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [112]
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“Both the acquisition of avoidance, and the reduction of the persistent conditioned threat reaction following avoidance learning, are blocked by the injection of protein synthesis inhibitors into the IL.”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [112]
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“The central nucleus and its brainstem-mediated behavioral output (freezing) are inhibited in avoidance learning (Moscarello and LeDoux, 2013).”
From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Moscarello and LeDoux, 2013
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“Research in rats has suggested that vmPFC activity may mediate the persistent effects of behavioral control on reduction of Pavlovian responses (Baratta et al., 2007; Moscarello and LeDoux, 2013).”
From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Moscarello and LeDoux, 2013
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“Our finding of a between-group difference in vmPFC BOLD signal during cue presentation in late Avoidance/Extinction and Retrieval (at an uncorrected threshold) is also consistent with the rodent literature suggesting a key role for the vmPFC in avoidance learning and its subsequent behavioral consequences (Baratta et al., 2007; Moscarello and LeDoux, 2013).”
From Active avoidance: Neural mechanisms and attenuation of pavlovian conditioned responding (2017) · cites this paper as Moscarello and LeDoux, 2013
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Metadata
- Authors
- Moscarello, J. M., & LeDoux, J. E.
- Affiliations
- New York University (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Moscarello, Justin M.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2013-02-27
- Volume
- 33
- Issue
- 9
- Pages
- 3815-3823
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3607300
- OpenAlex
- W2001417852
- Cited by
- 277
- References
- 38
- Citations by year
- 2026: 18 · 2025: 18 · 2024: 30 · 2023: 14 · 2022: 9 · 2021: 21 · 2020: 18 · 2019: 30 · 2018: 28 · 2017: 19 · 2016: 22 · 2015: 20 · 2014: 19 · 2013: 11
- FWCI
- 13.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- National Institute of Mental Health (R01MH038774, F32MH094061)
- National Institute on Drug Abuse (R01DA029053, R56DA029053)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- infralimbic cortex, central amygdala, instrumental avoidance, protein synthesis inhibition, avoidance memory
- MeSH terms
- Amygdala, Analysis of Variance, Animals, Anisomycin, Avoidance Learning, Conditioning, Classical, Conditioning, Operant, Cues, Electrolysis, Male, Muscimol, Neural Pathways, Protein Synthesis Inhibitors, Proto-Oncogene Proteins c-fos, Rats, Sprague-Dawley, Prefrontal Cortex, GABA Agonists, Rats
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