Glutamatergic mechanisms associated with stress-induced amygdala excitability and anxiety-related behavior
Open accessAbstract
The neural factors underlying individual differences in susceptibility to chronic stress remain poorly understood. Preclinical studies demonstrate that mouse strains vary greatly in anxiety-related responses to chronic stress in a manner paralleled by differential stress-induced changes in glutamatergic signaling in the basolateral amygdala (BLA). Previous work has also shown that alterations in the amygdala gene expression of the GluN1 NMDA and the GluK1 kainate receptors are associated with stress-induced alterations in anxiety-like behavior in the C57BL/6J mouse strain. Using in vivo behavioral pharmacological and ex vivo physiological approaches, the aim of the current study was to further elucidate changes in glutamate neurotransmission in the BLA caused by stress and to test the functional roles of GluN1 and GluK1 in mediating stress-related changes in behavior. Results showed that stress-induced alterations in anxiety-like behavior (light/dark exploration test) were absent following bilateral infusion of the GluK1 agonist ATPA into the BLA. Intra-BLA infusion of the competitive NMDA antagonist AP5 produced a generalized behavioral disinhibition/locomotor hyperactivity, irrespective of stress. Slice electrophysiological recordings showed that ATPA augmented BLA GABAergic neurotransmission and that stress increased the amplitude of network-dependent spontaneous excitatory postsynaptic currents and amplitude of GABAergic miniature inhibitory postsynaptic currents in BLA. These findings could indicate stress-induced BLA glutamatergic neuronal network hyperexcitability and a compensatory increase in GABAergic neurotransmission, suggesting that GluK1 agonism augmented GABAergic inhibition to prevent behavioral sequelae of stress. Current data could have implications for developing novel therapeutic approaches, including GluK1 agonists, for stress-related anxiety disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The BLA is generally hyperactive following chronic stress.
“The stress-induced attenuation of BLA→DMS activity was surprising because the BLA is, generally, hyperactive following chronic stress54–61 (c.f.62).”
From A dual-pathway architecture for stress to disrupt agency and promote habit (2025) · cites this paper as [60]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Krishnan, V., Han, M.-H., Graham, D. L., Berton, O., Renthal, W., Russo, S. J., LaPlant, Q., Graham, A., Lutter, M., Lagace, D. C., et al. (2007) · Cell · doi:10.1016/j.cell.2007.09.018 · Cited by 2,307 · cited 2× · see citing works
“…et al., 2012; Lack et al., 2008; Li and Rogawski, 1998; Wu et al., 2007), and more generally, in the context of a growing literature implicating amygdala glutamate signaling in stress-related anxiety (Cryan and Dev, 2007; Griebel and Holmes, 2013; Krishnan et al., 2007; Surget et al., 2009).”
BackgroundStress, memory and the amygdala
Roozendaal, B., McEwen, B. S., & Chattarji, S. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2651 · Cited by 1,760 · see citing works
Caspi, A., Hariri, A. R., Holmes, A., Uher, R., & Moffitt, T. E. (2010) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2010.09101452 · Cited by 1,346 · see citing works
Self-citationHeterogeneity of release probability, facilitation, and depletion at central synapses
Dobrunz, L. E., & Stevens, C. F. (1997) · Neuron · doi:10.1016/s0896-6273(00)80338-4 · Cited by 1,183 · see citing works
Walker, D. L., Ressler, K. J., Lu, K.-T., & Davis, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-06-02343.2002 · Cited by 815 · see citing works
Diverging neural pathways assemble a behavioural state from separable features in anxiety
Kim, S.-Y., Adhikari, A., Lee, S. Y., Marshel, J. H., Kim, C. K., Mallory, C. S., Lo, M., Pak, S., Mattis, J., Lim, B. K., et al. (2013) · Nature · doi:10.1038/nature12018 · Cited by 666 · see citing works
Crawley, J. N. (1981) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(81)90007-1 · Cited by 508 · see citing works
50 years of hurdles and hope in anxiolytic drug discovery
Griebel, G., & Holmes, A. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4075 · Cited by 414 · see citing works
Self-citationUchida, S., Hara, K., Kobayashi, A., Otsuki, K., Yamagata, H., Hobara, T., Suzuki, T., Miyata, N., & Watanabe, Y. (2011) · Neuron · doi:10.1016/j.neuron.2010.12.023 · Cited by 398 · see citing works
Gunduz-Cinar, O., MacPherson, K. P., Cinar, R., Gamble-George, J., Sugden, K., Williams, B., Godlewski, G., Ramikie, T. S., Gorka, A. X., Alapafuja, S. O., et al. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.72 · Cited by 307 · see citing works
Self-citationKullmann, D., Erdemli, G., & Asztely, F. (1996) · Neuron · doi:10.1016/s0896-6273(00)80178-6 · Cited by 299 · see citing works
Glucocorticoids Enhance the Excitability of Principal Basolateral Amygdala Neurons
Duvarci, S., & Paré, D. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.0680-07.2007 · Cited by 249 · see citing works
Mozhui, K., Karlsson, R.-M., Kash, T. L., Ihne, J., Norcross, M., Patel, S., Farrell, M. R., Hill, E. E., Graybeal, C., Martin, K. P., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5017-09.2010 · Cited by 226 · see citing works
Self-citationChronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding
Holmes, A., Fitzgerald, P. J., MacPherson, K. P., DeBrouse, L., Colacicco, G., Flynn, S. M., Masneuf, S., Pleil, K. E., Li, C., Marcinkiewcz, C. A., et al. (2012) · Nature Neuroscience · doi:10.1038/nn.3204 · Cited by 218 · see citing works
Self-citationSurget, A., Wang, Y., Leman, S., Ibargüen-Vargas, Y., Edgar, N. M., Griebel, G., Belzung, C., & Sibille, E. L. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.76 · Cited by 195 · see citing works
Feeling Strained? Influence of Genetic Background on Depression-Related Behavior in Mice: A Review
Jacobson, L. H., & Cryan, J. F. (2006) · Behavior Genetics · doi:10.1007/s10519-006-9106-3 · Cited by 168 · see citing works
Behavioral profile of wild mice in the elevated plus-maze test for anxiety
Holmes, A., Parmigiani, S., Ferrari, P. F., Palanza, P., & Rodgers, R. J. (2000) · Physiology & Behavior · doi:10.1016/s0031-9384(00)00373-5 · Cited by 148 · see citing works
Self-citationHumeau, Y., Reisel, D., Johnson, A. W., Borchardt, T., Jensen, V., Gebhardt, C., Bosch, V., Gass, P., Bannerman, D. M., Good, M. A., et al. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.2603-07.2007 · Cited by 147 · see citing works
Yang, R. J., Mozhui, K., Karlsson, R.-M., Cameron, H. A., Williams, R. W., & Holmes, A. (2008) · Neuropsychopharmacology · doi:10.1038/sj.npp.1301665 · Cited by 143 · see citing works
Self-citationIndividual differences in recovery from traumatic fear
Holmes, A., & Singewald, N. (2012) · Trends in Neurosciences · doi:10.1016/j.tins.2012.11.003 · Cited by 141 · see citing works
Self-citationLi, C., Pleil, K. E., Stamatakis, A. M., Busan, S., Vong, L., Lowell, B. B., Stuber, G. D., & Kash, T. L. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.015 · Cited by 139 · see citing works
Self-citationAlcohol Exposure Alters NMDAR Function in the Bed Nucleus of the Stria Terminalis
Kash, T. L., Baucum, A. J., Conrad, K. L., Colbran, R. J., & Winder, D. G. (2009) · Neuropsychopharmacology · doi:10.1038/npp.2009.69 · Cited by 133 · see citing works
Self-citationMultifaceted strain-specific effects in a mouse model of depression and of antidepressant reversal
Ibargüen-Vargas, Y., Surget, A., Touma, C., Palme, R., & Belzung, C. (2008) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2008.07.010 · Cited by 116 · see citing works
Braga, M. F. M., Aroniadou‐Anderjaska, V., Xie, J., & Li, H. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-02-00442.2003 · Cited by 112 · see citing works
Kainate receptor-mediated heterosynaptic facilitation in the amygdala
Li, H., Chen, A., Xing, G., Wei, M.-L., & Rogawski, M. A. (2001) · Nature Neuroscience · doi:10.1038/88432 · Cited by 111 · see citing works
Effects of stress and corticosterone on activity and plasticity in the amygdala
Kavushansky, A., & Richter‐Levin, G. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.21058 · Cited by 106 · see citing works
Karlsson, R., Tanaka, K., Heilig, M. A., & Holmes, A. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2008.05.001 · Cited by 100 · see citing works
Self-citationSingewald, N. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.02.003 · Cited by 98 · see citing works
GluR5 kainate receptor mediated synaptic transmission in rat basolateral amygdala in vitro
Li, H., & Rogawski, M. A. (1998) · Neuropharmacology · doi:10.1016/s0028-3908(98)00109-9 · Cited by 98 · see citing works
Sajdyk, T. J., & Shekhar, A. (1997) · PubMed · Cited by 96 · see citing works
Maroun, M., Ioannides, P. J., Bergman, K. L., Kavushansky, A., Holmes, A., & Wellman, C. L. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12259 · Cited by 86 · see citing works
Self-citationWu, L., Ko, S. W., Toyoda, H., Zhao, M., Xu, H., Vadakkan, K. I., Ren, M., Knifed, E., Shum, F. W. F., Quan, J., et al. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000167 · Cited by 82 · see citing works
Millstein, R. A., Ralph, R. J., Yang, R. J., & Holmes, A. (2006) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00172.x · Cited by 82 · see citing works
Self-citationWhittle, N., Hauschild, M., Lübec, G., Holmes, A., & Singewald, N. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.0849-10.2010 · Cited by 81 · see citing works
Self-citationCamp, M., Norcross, M. A., Whittle, N., Feyder, M. J., D’Hanis, W., Yilmazer‐Hanke, D., Singewald, N., & Holmes, A. (2009) · Genes Brain & Behavior · doi:10.1111/j.1601-183x.2009.00519.x · Cited by 69 · see citing works
Self-citationAroniadou‐Anderjaska, V., Pidoplichko, V. I., Figueiredo, T. H., Almeida-Suhett, C. P., Prager, E. M., & Braga, M. F. M. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.07.006 · Cited by 60 · see citing works
Nagura, H., Ishikawa, Y., Kobayashi, K., Takao, K., Tanaka, T., Nishikawa, K., Tamura, H., Shiosaka, S., Suzuki, H., Miyakawa, T., et al. (2012) · Molecular Brain · doi:10.1186/1756-6606-5-43 · Cited by 58 · see citing works
Sajdyk, T. J., & Shekhar, A. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37060-0 · Cited by 57 · see citing works
MK-801 Potentiates Ethanol's Effects on Locomotor Activity in Mice
Shen, E. (1998) · Pharmacology Biochemistry and Behavior · doi:10.1016/s0091-3057(97)00389-4 · Cited by 52 · see citing works
Ihne, J. L., Fitzgerald, P. J., Hefner, K. R., & Holmes, A. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.045 · Cited by 52 · see citing works
Self-citationLäck, A. K., Ariwodola, O. J., Chappell, A. M., Weiner, J. L., & McCool, B. A. (2008) · Neuropharmacology · doi:10.1016/j.neuropharm.2008.05.026 · Cited by 51 · see citing works
Christian, D., Alexander, N. J., Diaz, M. R., & McCool, B. A. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.09.004 · Cited by 50 · see citing works
Farley, S., Dumas, S., Mestikawy, S. E., & Giros, B. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.09.010 · Cited by 44 · see citing works
Reznikov, L. R., Reagan, L. P., & Fadel, J. R. (2008) · Brain Research · doi:10.1016/j.brainres.2008.12.022 · Cited by 43 · see citing works
Cryan, J. F., & Dev, K. K. (2008) · Handbook of behavioral neuroscience · doi:10.1016/s1569-7339(07)00013-6 · Cited by 25 · see citing works
Chen, Y.-C., & Holmes, A. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.182 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Chronic Stress Remodels Synapses in an Amygdala Circuit-Specific Manner
Zhang, J.-Y., Liu, T.-H., He, Y., Pan, H.-Q., Zhang, W.-H., Yin, X.-P., Tian, X.-L., Li, B.-M., Wang, X.-D., Holmes, A., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.06.019 · Cited by 183 · see citing works
Self-citationChronic stress dysregulates amygdalar output to the prefrontal cortex
Lowery-Gionta, E. G., Crowley, N. A., Bukalo, O., Silverstein, S., Holmes, A., & Kash, T. L. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.06.032 · Cited by 84 · see citing works
Self-citationPartridge, J. G., Forcelli, P. A., Luo, R., Cashdan, J. M., Schulkin, J., Valentino, R. J., & Vicini, S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.029 · Cited by 81 · see citing works
Hwa, L., Besheer, J., & Kash, T. (2017) · F1000Research · doi:10.12688/f1000research.9609.1 · Cited by 39 · see citing works
Self-citationA dual-pathway architecture for stress to disrupt agency and promote habit
Giovanniello, J. R., Paredes, N., Wiener, A., Ramírez-Armenta, K., Oragwam, C., Uwadia, H. O., Yu, A. L., Lim, K., Pimenta, J. S., Vilchez, G. E., et al. (2025) · Nature · doi:10.1038/s41586-024-08580-w · Cited by 30 · see citing works
Stress-induced blood brain barrier disruption: Molecular mechanisms and signaling pathways
Welcome, M. O., & Mastorakis, N. E. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.104769 · Cited by 139 · see citing works
- Authors
- Masneuf, S., Lowery-Gionta, E., Colacicco, G., Pleil, K. E., Li, C., Crowley, N., Flynn, S., Holmes, A., & Kash, T.
- Affiliations
- National Institutes of Health (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Kash, Thomas
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 85
- Pages
- 190-197
- ISSN
- 0028-3908 (ISSN-L)
- PMC
- PMC4170856
- OpenAlex
- W2059737837
- Cited by
- 69
- References
- 46
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 10 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 8 · 2016: 5 · 2015: 4 · 2014: 1
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- U.S. Department of Defense (W81XWH-10-1-0999)
- National Institute on Alcohol Abuse and Alcoholism
- Bowles Center for Alcohol Studies
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- chronic stress, anxiety-like behavior, basolateral amygdala, glutamatergic neurotransmission, atpA, AP5, GABAergic inhibition, excitatory postsynaptic currents, miniature inhibitory postsynaptic currents, C57BL/6J mice
- MeSH terms
- Animals, Anxiety, Exploratory Behavior, gamma-Aminobutyric Acid, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Synaptic Transmission, Restraint, Physical, Stress, Psychological, Receptors, N-Methyl-D-Aspartate, Akathisia, Drug-Induced, Receptors, Kainic Acid, Kainic Acid Receptors, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Glutamic Acid, Tissue Culture Techniques, Basolateral Nuclear Complex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
