Inhibition of projections from the basolateral amygdala to the entorhinal cortex disrupts the acquisition of contextual fear
Open accessAbstract
The development of excessive fear and/or stress responses to environmental cues such as contexts associated with a traumatic event is a hallmark of post-traumatic stress disorder (PTSD). The basolateral amygdala (BLA) has been implicated as a key structure mediating contextual fear conditioning. In addition, the hippocampus has an integral role in the encoding and processing of contexts associated with strong, salient stimuli such as fear. Given that both the BLA and hippocampus play an important role in the regulation of contextual fear conditioning, examining the functional connectivity between these two structures may elucidate a role for this pathway in the development of PTSD. Here, we used optogenetic strategies to demonstrate that the BLA sends a strong glutamatergic projection to the hippocampal formation through the entorhinal cortex (EC). Next, we photoinhibited glutamatergic fibers from the BLA terminating in the EC during the acquisition or expression of contextual fear conditioning. In mice that received optical inhibition of the BLA-to-EC pathway during the acquisition session, we observed a significant decrease in freezing behavior in a context re-exposure session. In contrast, we observed no differences in freezing behavior in mice that were only photoinhibited during the context re-exposure session. These data demonstrate an important role for the BLA-to-EC glutamatergic pathway in the acquisition of contextual fear conditioning.
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BLA projections to the hippocampal formation through the entorhinal cortex are necessary for the acquisition of contextual fear memories, as photoinhibition of these terminals during learning blocks freezing during context reexposure.
“for example, BLA projections to the hippocampal formation through the entorhinal cortex are necessary for the acquisition of contextual fear memories, as photoinhibition of these terminals during learning blocks freezing during context reexposure90.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [90]
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Cites
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037/0735-7044.106.2.274 · Cited by 3,292 · see citing works
Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning.
Phillips, R. G., & LeDoux, J. E. (1992) · Behavioral Neuroscience · doi:10.1037//0735-7044.106.2.274 · Cited by 3,262 · see citing works
The role of the amygdala in fear and anxiety
Davis, M. (1992) · Annual Review of Neuroscience · doi:10.1146/annurev.ne.15.030192.002033 · Cited by 2,357 · see citing works
Context, ambiguity, and unlearning: sources of relapse after behavioral extinction
Bouton, M. E. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01546-9 · Cited by 1,662 · see citing works
The contextual brain: implications for fear conditioning, extinction and psychopathology
Maren, S., Phan, K. L., & Liberzon, I. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3492 · Cited by 1,547 · see citing works
Conditional and unconditional components of post-shock freezing
Fanselow, M. S. (1980) · Pavlovian Journal of Biological Science · doi:10.1007/bf03001163 · Cited by 1,153 · see citing works
Crouching as an index of fear.
Blanchard, R. J., & Blanchard, D. C. (1969) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0026779 · Cited by 1,077 · see citing works
Molecular and Cellular Approaches for Diversifying and Extending Optogenetics
Gradinaru, V., Zhang, F., Ramakrishnan, C., Mattis, J., Prakash, R., Diester, I., Goshen, I., Thompson, K. R., & Deisseroth, K. A. (2010) · Cell · doi:10.1016/j.cell.2010.02.037 · Cited by 999 · see citing works
Pitkänen, A., Pikkarainen, M., Nurminen, N., & Ylinen, A. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06738.x · Cited by 962 · see citing works
Switching on and off fear by distinct neuronal circuits
Herry, C., Ciocchi, S., Senn, V., Demmou, L., Müller, C., & Lüthi, A. (2008) · Nature · doi:10.1038/nature07166 · Cited by 950 · see citing works
Bouton, M. E., & King, D. A. (1983) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.9.3.248 · Cited by 771 · see citing works
Innate and conditioned reactions to threat in rats with amygdaloid lesions.
Blanchard, D. C., & Blanchard, R. J. (1972) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0033521 · Cited by 753 · see citing works
Distinct extended amygdala circuits for divergent motivational states
Jennings, J. H., Sparta, D. R., Stamatakis, A. M., Ung, R. L., Pleil, K. E., Kash, T. L., & Stuber, G. D. (2013) · Nature · doi:10.1038/nature12041 · Cited by 704 · cited 4× · see citing works
“PATCH-CLAMP ELECTROPHYSIOLOGY Brain slice preparation and general methods for patchclamp electrophysiology were conducted as previously described (Stamatakis and Stuber, 2012; van Zessen et al., 2012; Jennings et al., 2013).”
BackgroundMethodInfluentialSelf-citationAnagnostaras, S., Maren, S., & Fanselow, M. S. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-03-01106.1999 · Cited by 656 · see citing works
Kim, J. J., Rison, R. A., & Fanselow, M. S. (1993) · Behavioral Neuroscience · doi:10.1037/0735-7044.107.6.1093 · Cited by 615 · see citing works
Activation of VTA GABA Neurons Disrupts Reward Consumption
van Zessen, R., Phillips, J. L., Budygin, E. A., & Stuber, G. D. (2012) · Neuron · doi:10.1016/j.neuron.2012.02.016 · Cited by 609 · see citing works
Self-citationThe functional neuroanatomy of PTSD: a critical review
Liberzon, I., & Sripada, C. S. (2007) · Progress in Brain Research · doi:10.1016/s0079-6123(07)67011-3 · Cited by 594 · see citing works
BLA to vHPC inputs modulate anxiety-related behaviors
Felix-Ortiz, A. C., Beyeler, A., Seo, C., Leppla, C. A., Wildes, C. P., & Tye, K. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.06.016 · Cited by 592 · see citing works
Amygdala central nucleus lesions: Effect on heart rate conditioning in the rabbit
Kapp, B. S., Frysinger, R. C., Gallagher, M., & Haselton, J. R. (1979) · Physiology & Behavior · doi:10.1016/0031-9384(79)90304-4 · Cited by 590 · see citing works
Activation of lateral habenula inputs to the ventral midbrain promotes behavioral avoidance
Stamatakis, A. M., & Stuber, G. D. (2012) · Nature Neuroscience · doi:10.1038/nn.3145 · Cited by 564 · see citing works
Self-citationNeurobiology of fear responses: the role of the amygdala
Davis, M. (1997) · Journal of Neuropsychiatry · doi:10.1176/jnp.9.3.382 · Cited by 562 · see citing works
Hitchcock, J., & Davis, M. (1986) · Behavioral Neuroscience · doi:10.1037/0735-7044.100.1.11 · Cited by 541 · see citing works
Hitchcock, J. M., & Davis, M. (1986) · Behavioral Neuroscience · doi:10.1037//0735-7044.100.1.11 · Cited by 536 · see citing works
Amygdala inputs to the ventral hippocampus bidirectionally modulate social behavior
Felix-Ortiz, A. C., & Tye, K. M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.4257-13.2014 · Cited by 473 · see citing works
Goosens, K. A., & Maren, S. (2001) · Learning & Memory · doi:10.1101/lm.37601 · Cited by 451 · see citing works
Construction of implantable optical fibers for long-term optogenetic manipulation of neural circuits
Sparta, D. R., Stamatakis, A. M., Phillips, J. L., Hovelsø, N., van Zessen, R., & Stuber, G. D. (2012) · Nature Protocols · doi:10.1038/nprot.2011.413 · Cited by 394 · see citing works
Self-citationThe lifetime prevalence of traumatic events and posttraumatic stress disorder in the Netherlands
de Vries, G., & Olff, M. (2009) · Journal of Traumatic Stress · doi:10.1002/jts.20429 · Cited by 390 · see citing works
Hall, J., Thomas, K. L., & Everitt, B. J. (2001) · Journal of Neuroscience · doi:10.1523/jneurosci.21-06-02186.2001 · Cited by 381 · see citing works
Maren, S., & Fanselow, M. S. (1997) · Neurobiology of Learning and Memory · doi:10.1006/nlme.1996.3752 · Cited by 324 · see citing works
Orsini, C. A., Kim, J. H., Knapska, E., & Maren, S. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4095-11.2011 · Cited by 315 · see citing works
Effects of context manipulation on memory and reversal learning in rats with hippocampal lesions.
Winocur, G., & Olds, J. (1978) · Journal of Comparative and Physiological Psychology · doi:10.1037/h0077468 · Cited by 296 · see citing works
Altered Processing of Contextual Information during Fear Extinction in PTSD: An fMRI Study
Rougemont-Bücking, A., Linnman, C., Zeffiro, T. A., Zeidan, M. A., Lebron-Milad, K., Rodriguez-Romaguera, J., Rauch, S. L., Pitman, R. K., & Milad, M. R. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00152.x · Cited by 292 · see citing works
Mammalian brain substrates of aversive classical conditioning.
Lavond, D., Kim, J. J., & Thompson, R. F. (1993) · Annual Review of Psychology · doi:10.1146/annurev.ps.44.020193.001533 · Cited by 258 · see citing works
Contextual control over conditioned responding in an extinction paradigm.
Harris, J. A., Jones, M. L., Bailey, G. K., & Westbrook, R. F. (2000) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037//0097-7403.26.2.174 · Cited by 210 · see citing works
Functional anatomy of neural circuits regulating fear and extinction
Knapska, E., Macias, M., Mikosz, M., Nowak, A., Owczarek, D., Wawrzyniak, M., Pieprzyk, M., Cymerman, I. A., Werka, T., Sheng, M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202087109 · Cited by 187 · see citing works
Epigenetic Mechanisms in Learned Fear: Implications for PTSD
Zovkic, I. B., & Sweatt, J. D. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.79 · Cited by 186 · see citing works
Gentile, C. G., Jarrell, T. W., Teich, A. H., McCabe, P. M., & Schneiderman, N. (1986) · Behavioural Brain Research · doi:10.1016/0166-4328(86)90226-3 · Cited by 153 · see citing works
Contextual control over conditioned responding in an extinction paradigm.
Harris, J. A., Jones, M. L., Bailey, G. K., et al. (2000) · Journal of Experimental Psychology Animal Behavior Processes · doi:10.1037/0097-7403.26.2.174 · Cited by 129 · see citing works
Hippocampal regulation of context-dependent neuronal activity in the lateral amygdala.Preprint
Maren, S., & Hobin, J. A. (2007) · Learning & memory (Cold Spring Harbor, N.Y.) · doi:10.1101/lm.477007 · Cited by 128 · see citing works
Zimmerman, J. M., & Maren, S. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07223.x · Cited by 127 · see citing works
Koch, S. B. J., van Zuiden, M., Nawijn, L., Frijling, J. L., Veltman, D. J., & Olff, M. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2013.11.018 · Cited by 123 · see citing works
Goosens, K. A., & Maren, S. (2003) · Behavioral Neuroscience · doi:10.1037/0735-7044.117.4.738 · Cited by 112 · see citing works
(1998) · CRC Press eBooks · doi:10.1201/9781420001136-33 · Cited by 63 · see citing works
Majchrzak, M. J., Ferry, B., Marchand, A. R., Herbeaux, K., Seillier, A., & Barbelivien, A. (2005) · Hippocampus · doi:10.1002/hipo.20138 · Cited by 50 · see citing works
Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats
Ji, J.-Z., & Maren, S. (2008) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.07.011 · Cited by 37 · see citing works
Ueki, A., Miwa, C., & Miyoshi, K. (1994) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(94)90236-4 · Cited by 36 · see citing works
Mammalian Brain Substrates of Aversive Classical Conditioning
Lavond, D. G. (1993) · Annual Review of Psychology · doi:10.1146/annurev.psych.44.1.317 · Cited by 14 · see citing works
A Brain Structure: The Hippocampus.
Nadel, L. (1987) · Science · doi:10.1126/science.235.4796.1682a · Cited by 5 · see citing works
A Brain Structure: The Hippocampus.
Nadel, L. (1987) · Science · doi:10.1126/science.1682a · Cited by 3 · see citing works
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Lüthi, A., & Lüscher, C. (2014) · Nature Neuroscience · doi:10.1038/nn.3849 · Cited by 192 · see citing works
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Steinberg, E. E., Christoffel, D. J., Deisseroth, K., & Malenka, R. C. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.004 · Cited by 92 · see citing works
- Authors
- Sparta, D. R., Smithuis, J., Stamatakis, A. M., Jennings, J. H., Kantak, P. A., Ung, R. L., & Stuber, G. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Stuber, Garret D.
- Venue
- Frontiers in Behavioral Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2014-05-06
- Volume
- 8
- Pages
- 129-129
- ISSN
- 1662-5153 (ISSN-L)
- PMC
- PMC4018552
- OpenAlex
- W2118979149
- Cited by
- 75
- References
- 49
- Citations by year
- 2026: 4 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 11 · 2020: 4 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 9 · 2015: 11 · 2014: 5
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Behavioral Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UNC Libraries
- Funders
- Whitehall Foundation
- National Alliance for Research on Schizophrenia and Depression
- Foundation of Hope for Research and Treatment of Mental Illness
- National Institute on Alcohol Abuse and Alcoholism (P50AA011605, AA011605, AA021417, AA 007573, R00AA021417, AA022234, K99AA021417, R01AA022234, P60AA011605, T32AA007573)
- National Institute on Drug Abuse (F31DA034472, R01DA032750, DA029325, R21DA029325, DA032750)
- National Institute of Neurological Disorders and Stroke (P30NS045892)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD079124)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- basolateral amygdala, entorhinal cortex, contextual fear conditioning, glutamatergic projections, hippocampus, post-traumatic stress disorder, fear acquisition, photoinhibition, optogenetics, freezing behavior
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