The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
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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Citations
Cites
LeDoux, J. E. (2000) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.23.1.155 · Cited by 8,444
Self-citationCoping styles in animals: current status in behavior and stress-physiology
Koolhaas, J. M., Korte, S. M., De Boer, S. F., Van Der Vegt, B. J., Van Reenen, C. G., Hopster, H., De Jong, I. C., Ruis, M. A. W., & Blokhuis, H. J. (1999) · Neuroscience & Biobehavioral Reviews · doi:10.1016/s0149-7634(99)00026-3 · Cited by 2,875
Neurons in medial prefrontal cortex signal memory for fear extinction
Milad, M. R., & Quirk, G. J. (2002) · Nature · doi:10.1038/nature01138 · Cited by 1,836 · cited 1×
“Although ilPFC can attenuate CeA activity and the reactive behaviors it governs (Milad and Quirk, 2002; Quirk et al., 2003; Likhtik et al., 2005), this must occur via an intervening mechanism for excitatory cortical inputs to inhibit amygdalar outputs.”
BackgroundSpecies-specific defense reactions and avoidance learning
Bolles, R. C. (1970) · Psychological Review · doi:10.1037/h0028589 · Cited by 1,610
Rethinking the Emotional Brain
LeDoux, J. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.004 · Cited by 1,594 · cited 1×
“Thus, by gaining control over US delivery, subjects successfully inhibit the expression of deeply instated behavioral reactions that normally prevail in situations of expected threat (Fanselow and Lester, 1988; Blanchard et al., 2005; LeDoux, 2012).”
BackgroundSelf-citationLeDoux, J., Iwata, J., Cicchetti, P., & Reis, D. (1988) · The Journal of Neuroscience · doi:10.1523/jneurosci.08-07-02517.1988 · Cited by 1,580
Self-citationSesack, S. R., Deutch, A. Y., Roth, R. H., & Bunney, B. S. (1989) · Journal of Comparative Neurology · doi:10.1002/cne.902900205 · Cited by 1,568
Neuronal signalling of fear memory
Maren, S., & Quirk, G. J. (2004) · Nature Reviews Neuroscience · doi:10.1038/nrn1535 · Cited by 1,428
Sierra-Mercado, D., Padilla-Coreano, N., & Quirk, G. J. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2010.184 · Cited by 1,190
Neural organization of the defensive behavior system responsible for fear
Fanselow, M. S. (1994) · Psychonomic Bulletin & Review · doi:10.3758/bf03210947 · Cited by 1,000
Research works printed but not linked: 1
- Pavlov IP (1927) Conditioned reflexes (Routledge and Kegan Paul, London).
Cited by
Sorted by citations
Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective
Grupe, D. W., & Nitschke, J. B. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3524 · Cited by 2,007
LeDoux, J. E. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1400335111 · Cited by 891
Self-citationBrain circuit dysfunction in post-traumatic stress disorder: from mouse to man
Fenster, R. J., Lebois, L. A. M., Ressler, K. J., & Suh, J. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0039-7 · Cited by 456
LeDoux, J. E., & Daw, N. D. (2018) · Nature reviews. Neuroscience · doi:10.1038/nrn.2018.22 · Cited by 405
Self-citationAvoidance learning: a review of theoretical models and recent developments
Krypotos, A. (2015) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2015.00189 · Cited by 402
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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