Active Avoidance Learning Requires Prefrontal Suppression of Amygdala-Mediated Defensive Reactions
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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.
“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
The Discussion reports that acquiring control over an aversive outcome suppresses conditioned freezing, including when the cue is presented where avoidance is impossible. It implicates the infralimbic prefrontal cortex, a rodent vmPFC region, but the paper does not establish the striatum’s involvement in this effect. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe vmPFC toggles between amygdala output paths, shifting information flow to promote aversively motivated action instead of Pavlovian freezing responses.
“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
The Discussion (page unavailable in our copy) proposes that infralimbic prefrontal cortex inhibits central-amygdala-mediated freezing, allowing active avoidance to predominate. It does not describe the vmPFC toggling between distinct amygdala output paths or shifting information flow between them. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPlasticity in the IL is critical for the persistent reduction of conditioned responses with avoidance.
“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]
Avoidance learning results in a persistent reduction in the passive conditioned response, even when the avoidance action is no longer available.
“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]
Acquisition of avoidance and reduction of the persistent conditioned threat reaction following avoidance learning are blocked by injection of protein synthesis inhibitors into the IL.
“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]
The central nucleus and its brainstem-mediated behavioral output (freezing) are inhibited in avoidance learning.
“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
Research in rats has suggested that vmPFC activity may mediate the persistent effects of behavioral control on reduction of Pavlovian responses.
“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
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 consistent with the rodent literature suggesting a key role for the vmPFC in avoidance learning and its subsequent behavioral consequences.
“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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- 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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