Role of the Amygdala in Fear Extinction Measured with Potentiated Startle
Abstract
A bstract: Although much is now known about the neural basis of excitatory fear conditioning, much less is known about the neural basis of inhibitory conditioning. One type of inhibitory conditioning is extinction, a process in which stimuli that elicit fear by virtue of previous associations with aversive stimuli such as shock (excitatory fear conditioning) are now presented in the absence of the aversive stimuli (extinction training). As a result, the ability of the conditioned stimulus to elicit fear gradually diminishes. Extinction is different from forgetting and does not reflect an erasure of the original fear memory. Instead, extinction is an active form of inhibitory learning that competes with excitatory fear conditioning. Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA‐receptor‐linked mitogen‐activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist D‐cycloserine facilitates extinction after either systemic administration or intra‐amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because D‐cycloserine is a widely available and safe compound, D‐cycloserine or similar agents might be usefully combined with traditional extinction‐based approaches in the treatment of clinical fear.
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The neural circuitry underlying threat and fear-related behaviors in mammals, including the amygdala-hippocampus-medial prefrontal circuit, is among the most well-understood behavioral circuits in neuroscience.
“the neural circuitry underlying threat and fear-related behaviors in mammals, including the amygdala–hippocampus–medial prefrontal circuit, is among the most well-understood behavioral circuits in neuroscience [11–14].”
From Prefrontal cortex, amygdala, and threat processing: implications for PTSD (2022) · cites this paper as [11]
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“In particular, the fear-potentiated startle paradigm, the augmentation of the ASR in an aversive emotional state, has been used since then to investigate the pharmacological and neuronal basics of fear in both humans and rats (eg, Davis, 1998; Lang, 1995; Davis et al, 2003; Norrholm et al, 2006).”
MethodAkirav, I. (2007) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301050 · Cited by 42 · see citing works
“This view is compatible with evidence that GABAA receptor agonists interrupt, whereas NMDA receptor agonists facilitate extinction of fear memories (Davis et al, 2003; Pereira et al, 1989; Santini et al, 2001; Walker et al, 2002).”
BackgroundInfluentialPharmacological Findings on the Biochemical Bases of Memory Processes: A General View
Izquierdo, I., Cammarota, M., Medina, J., & Bevilaqua, L. (2004) · Journal of Neural Transplantation and Plasticity · doi:10.1155/np.2004.159 · Cited by 41 · see citing works
Developmental Epidemiology of PTSD
Koenen, K. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1364.020 · Cited by 40 · see citing works
Harris, A. C., Rothwell, P. E., & Gewirtz, J. C. (2008) · Psychopharmacology · doi:10.1007/s00213-007-0998-2 · Cited by 38 · see citing works
“Given that startle is increased during states of fear and anxiety in both humans and animals (Lang et al. 2000; Davis et al. 2003), “withdrawal-potentiated startle” may reflect the anxiogenic effects of withdrawal.”
Ressler, K., McCullough, K., Daskalakis, N., Gafford, G. M., & Morrison, F. (2017) · bioRxiv · doi:10.1038/s41398-018-0190-y · Cited by 37 · see citing works
Rea, K., Roche, M., & Finn, D. (2011) · Journal of Pain · doi:10.1016/j.jpain.2010.12.010 · Cited by 37 · see citing works
BEVILAQUA, L., DASILVA, W., MEDINA, J., IZQUIERDO, I., & CAMMAROTA, M. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.03.005 · Cited by 35 · see citing works
Vega-Torres, J., Haddad, E., Lee, J. B., Kalyan-Masih, P., George, W., Pérez, L., Vázquez, D. M. P., Torres, Y. A., Santana, J. M. S., Obenaus, A., et al. (2018) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2018.01.011 · Cited by 35 · see citing works
Lushchak, O. V., Strilbytska, O. M., Koliada, A. K., & Storey, K. B. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2022.1094076 · Cited by 39 · see citing works
“For example, the amygdala lateral nucleus is known to play a central role in triggering fear (Davis et al., 2003; Morey et al., 2012).”
BackgroundLehner, M., Wisłowska-Stanek, A., Taracha, E., Maciejak, P., Szyndler, J., Skórzewska, A., Turzyńska, D., Sobolewska, A., Hamed, A., Bidziński, A., et al. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.08.014 · Cited by 33 · see citing works
Candidate genes for panic disorder: insight from human and mouse genetic studies
Gratacòs, M., Sahún, I., Gallego, X., Amador‐Arjona, A., Estivill, X., & Dierssen, M. (2007) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2007.00318.x · Cited by 33 · see citing works
“During normal functioning, the amygdala continuously compares incoming sensory stimuli with previously learned aversive stimuli (Davis et al. 2003; LeDoux 1996), leading to the activation of appropriate conditioned response pathways.”
BackgroundDetert, J. A., Kampa, N. D., & Moyer, J. (2008) · Behavioral Neuroscience · doi:10.1037/a0013512 · Cited by 31 · see citing works
Appetitive odor-cue conditioning attenuates the acoustic startle response in rats.
Schneider, M., & Spanagel, R. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2007.12.017 · Cited by 31 · see citing works
Birk, L. (2004) · Journal of Clinical Psychology · doi:10.1002/jclp.20044 · Cited by 31 · see citing works
Early-Life Experiences: Enduring Behavioral, Neurological, and Endocrinological Consequences
Romeo, R., Tang, A. C., & Sullivan, R. (2009) · Elsevier eBooks · doi:10.1016/b978-008088783-8.00062-0 · Cited by 30 · see citing works
Autismo: tratamentos psicofarmacológicos e áreas de interesse para desenvolvimentos futuros
Nikolov, R., Jonker, J., & Scahill, L. D. (2006) · Brazilian Journal of Psychiatry · doi:10.1590/s1516-44462006000500006 · Cited by 41 · see citing works
Organization of Neural Systems for Aversive Information Processing: Pain, Error, and Punishment
Kobayashi, S. (2012) · Frontiers in Neuroscience · doi:10.3389/fnins.2012.00136 · Cited by 27 · see citing works
“…escape, and freezing) to an innocuous stimulus (i.e., a tone) that predicts a noxious stimulus (i.e., electric shock), and amygdala lesions cause behavioral impairments in these aversive conditioning (Pellegrino, 1968; Slotnick, 1973; Wilensky et al., 1999; Davis et al., 2003; Blair et al., 2005).”
BackgroundBuckwalter, J. A., Schumann, C. M., & Van Hoesen, G. W. (2008) · Experimental Brain Research · doi:10.1007/s00221-007-1203-x · Cited by 26 · see citing works
“There is an abundance of evidence from animal (LeDoux 2000; Davis et al. 2003; Bauman et al. 2004) and human (Adolphs et al. 1994; Adolphs et al. 1995; Whalen et al. 1998; Buchel and Dolan 2000; Whalen et al. 2004) studies to implicate the amygdala in emotional processing as well, particularly the…”
BackgroundBoecker, L., & Pauli, P. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.019 · Cited by 26 · see citing works
Roth, T., Moriceau, S., & Sullivan, R. (2006) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.301206 · Cited by 22 · see citing works
“…hippocampus, frontal cortex, and amygdala, with the basolateral complex of the amygdala serving as a potential site for stimuli associations (LeDoux et al. 1990; Fendt and Fanselow 1999; Schafe et al. 2000; Maren 2001; Davis et al. 2003; Fanselow and Poulos 2005; Rudy and Matus-Amat 2005).”
BackgroundEffects of reinforcement schedule on facilitation of operant extinction by chlordiazepoxide.
Leslie, J., Shaw, D. R., Gregg, G., McCormick, N., Reynolds, D., & Dawson, G. (2005) · Journal of The Experimental Analysis of Behavior · doi:10.1901/jeab.2005.71-04 · Cited by 22 · see citing works
“Specific procedures used include conditioned freezing (Ledgerwood, Richardson, & Cranney, 2004) and the fear-potentiated startle ( Davis, Walker, & Myers, 2003 ).”
MethodFear Conditioning in Rodents and Humans
Milad, M., Igoe, S. A., & Orr, S. (2011) · Neuromethods · doi:10.1007/978-1-60761-883-6_5 · Cited by 21 · see citing works
Neural circuits involved in the renewal of extinguished fear
Chen, W.-H., Wang, Y., Wang, X.-Q., & Li, H. (2017) · IUBMB Life - A Journal of the International Union of Biochemistry and Molecular Biology · doi:10.1002/iub.1636 · Cited by 20 · see citing works
Browne, C. A., Hanke, J., Rose, C., Walsh, I., Foley, T., Clarke, G., Schwegler, H., Cryan, J., & Yilmazer-Hanke, D. (2014) · Stress · doi:10.3109/10253890.2014.954104 · Cited by 20 · see citing works
“Fear extinction is the gradual weakening of this learned fear response upon repetitive presentations of the CS in the absence of the US (Davis et al., 2003; Sotres-Bayon et al., 2004).”
BackgroundAbu-Ghanem, Y., Cohen, H., Buskila, Y., Grauer, E., & Amitai, Y. (2008) · Neuroscience · doi:10.1016/j.neuroscience.2008.07.043 · Cited by 20 · see citing works
“The ASR is often associated with fear reactivity and is known to be enhanced by stress (Davis et al., 2003).”
BackgroundToba, S., Tamura, Y., Kumamoto, K., Yamada, M., Takao, K., Hattori, S., Miyakawa, T., Kataoka, Y., Azuma, M., Hayasaka, K., et al. (2013) · Scientific Reports · doi:10.1038/srep01224 · Cited by 19 · see citing works
Storch, E., McKay, D., Reid, J., Geller, D., Goodman, W., Lewin, A., & Murphy, T. (2010) · Child & Youth Care Forum · doi:10.1007/s10566-010-9094-6 · Cited by 17 · see citing works
“and memory (Davis 2000; Davis et al. 2003; Myers and Davis 2002).”
BackgroundInfluential
- Authors
- DAVIS, M., WALKER, D. L., & MYERS, K. M.
- Affiliations
- Emory University (US)
- Corresponding author
- DAVIS, MICHAEL
- ORCID
- WALKER, DAVID L.
- Venue
- Annals of the New York Academy of Sciences
- Publisher
- Wiley
- Published
- 2003-04
- Volume
- 985
- Issue
- 1
- Pages
- 218-232
- ISSN
- 0077-8923 (ISSN-L)
- 1749-6632
- OpenAlex
- W2154648089
- Cited by
- 152
- References
- 0
- Citations by year
- 2026: 2 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 7 · 2016: 3 · 2015: 3 · 2014: 9 · 2013: 9 · 2012: 5
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of the New York Academy of Sciences (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (MH59906, MH-57250, R01MH057250, P50MH052384, R01MH059906, P50MH058922, MH58922, MH 47840, MH-52384)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- amygdala, fear extinction, inhibitory conditioning, NMDA receptor, D-cycloserine, mitogen-activated protein kinase, extinction learning, fear memory
- MeSH terms
- Amygdala, Animals, Extinction, Psychological, Fear, Reflex, Startle, Receptors, N-Methyl-D-Aspartate
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