Prolonged and site-specific over-expression of corticotropin-releasing factor reveals differential roles for extended amygdala nuclei in emotional regulation
Abstract
Corticotropin-releasing factor (CRF) has a key role in the central stress response, and altered levels of this neuropeptide are linked to stress-related psychopathologies such as anxiety and depression. These disorders are associated with the inability to properly regulate stress response, specifically following exposure to prolonged stressful stimuli. Therefore, the current study assessed the effects of prolonged and site-specific over-expression of CRF, which mimics the state of chronic production, in extended amygdala nuclei that are known to be involved in mediating anxiety-like states. We first constructed and generated lentiviruses that overexpress (OE) CRF in a robust and stable manner, and then generated two male mouse models continuously over-expressing CRF, either at the central nucleus of the amygdala (CeA), or at the dorsolateral subdivision of the bed nucleus of the stria terminalis (BNSTdl). After 4 months, behavioral assessments were conducted for anxiety and depressive indices on these mice. Surprisingly, prolonged CRF OE at the CeA attenuated stress-induced anxiety-like behaviors, whereas prolonged CRF OE in the BNSTdl increased depressive-like behaviors, without affecting anxiety levels. These results show possible differential roles for CRF expressed by distinct loci of the extended amygdala, in mediating stress-induced emotional behaviors.
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The central amygdala nucleus (CEA) has been implicated in learning and expression of fear responses, as well as the expression of stress-induced anxiety behaviors.
“Functionally, CEA has been implicated in learning and expression of fear responses,105, 106, 107 as well as the expression of stress-induced anxiety behaviors.108, 109, 110, 111, 112, 113”
From Preferential loss of dorsal-hippocampus synapses underlies memory impairments provoked by short, multimodal stress (2014) · cites this paper as [111]
Cites
In Vivo Gene Delivery and Stable Transduction of Nondividing Cells by a Lentiviral Vector
Naldini, L., Blömer, U., Gallay, P., Ory, D., Mulligan, R., Gage, F. H., Verma, I. M., & Trono, D. (1996) · Science · doi:10.1126/science.272.5259.263 · Cited by 4,903 · see citing works
Stress and the brain: from adaptation to disease
de Kloet, E. R., Joëls, M., & Holsboer, F. (2005) · Nature Reviews Neuroscience · doi:10.1038/nrn1683 · Cited by 4,621 · see citing works
Vale, W., Spiess, J., Rivier, C., & Rivier, J. (1981) · Science · doi:10.1126/science.6267699 · Cited by 3,965 · see citing works
Vale, W., Spiess, J., RIVIER, C. L., & Rivier, J. (1982) · Obstetrical & Gynecological Survey · doi:10.1097/00006254-198205000-00013 · Cited by 3,904 · see citing works
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002) · Neuron · doi:10.1016/s0896-6273(02)00653-0 · Cited by 3,217 · see citing works
The molecular neurobiology of depression
Krishnan, V., & Nestler, E. J. (2008) · Nature · doi:10.1038/nature07455 · Cited by 2,889 · see citing works
The Concepts of Stress and Stress System Disorders: Overview of Physical and Behavioral Homeostasis
Chrousos, G. P. (1992) · JAMA · doi:10.1001/jama.1992.03480090092034 · Cited by 2,689 · see citing works
Swanson, L. W., Sawchenko, P. E., Rivier, J., & Vale, W. W. (2008) · Neuroendocrinology · doi:10.1159/000123454 · Cited by 1,953 · see citing works
Joëls, M., & Baram, T. Z. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2632 · Cited by 1,521 · see citing works
Naldini, L., Blömer, U., Gage, F. H., Trono, D., & Verma, I. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11382 · Cited by 1,499 · see citing works
The role of corticotropin-releasing factor in depression and anxiety disorders
Arborelius, L., Owens, M., Plotsky, P., & Nemeroff, C. (1999) · Journal of Endocrinology · doi:10.1677/joe.0.1600001 · Cited by 1,378 · see citing works
Timpl, P., Spanagel, R., Sillaber, I., Kresse, A., Reul, J. M. H. M., Stalla, G. K., Blanquet, V., Steckler, T., Holsboer, F., & Wurst, W. (1998) · Nature Genetics · doi:10.1038/520 · Cited by 919 · see citing works
Estelle, F., & Simons, R. (1994) · Drug Safety · doi:10.2165/00002018-199410050-00002 · Cited by 751 · see citing works
Corticotropin releasing factor produces behavioural activation in rats
Sutton, R., Koob, G., le Moal, M., Rivier, J., & Vale, W. (1982) · Nature · doi:10.1038/297331a0 · Cited by 744 · see citing works
Topography of projections from amygdala to bed nuclei of the stria terminalis
Dong, H.-W., Petrovich, G. D., & Swanson, L. W. (2001) · Brain Research Reviews · doi:10.1016/s0165-0173(01)00079-0 · Cited by 714 · see citing works
Glucocorticoids, depression, and mood disorders: Structural remodeling in the brain
McEwen, B. S. (2005) · Metabolism · doi:10.1016/j.metabol.2005.01.008 · Cited by 687 · see citing works
Holsboer, F. (1999) · Journal of Psychiatric Research · doi:10.1016/s0022-3956(98)90056-5 · Cited by 654 · see citing works
Corticotropin-Releasing Factor: Actions on the Sympathetic Nervous System and Metabolism*
Brown, M. R., Fisher, L. A., Spiess, J., RIVIER, C. L., Rivier, J., & Vale, W. (1982) · Endocrinology · doi:10.1210/endo-111-3-928 · Cited by 651 · see citing works
Walker, D. L., & Davis, M. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-23-09375.1997 · Cited by 627 · see citing works
Are different parts of the extended amygdala involved in fear versus anxiety?
Davis, M. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00288-1 · Cited by 545 · see citing works
Hitchcock, J., & Davis, M. (1986) · Behavioral Neuroscience · doi:10.1037/0735-7044.100.1.11 · Cited by 541 · see citing works
Rivier, C., & Vale, W. (1983) · Nature · doi:10.1038/305325a0 · Cited by 539 · 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
A role for corticotropin releasing factor and urocortin in behavioral responses to stressors
Koob, G. F., & Heinrichs, S. C. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01991-5 · Cited by 530 · see citing works
Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need
Muglia, L., Jacobson, L., Dikkes, P., & Majzoub, J. A. (1995) · Nature · doi:10.1038/373427a0 · Cited by 524 · see citing works
Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression
Reul, J. M. H. M. (2002) · Current Opinion in Pharmacology · doi:10.1016/s1471-4892(01)00117-5 · Cited by 515 · see citing works
Campeau, S., & Davis, M. (1995) · The Journal of Neuroscience · doi:10.1523/jneurosci.15-03-02301.1995 · Cited by 479 · see citing works
Stenzel‐Poore, M. P., Heinrichs, S. C., Rivest, S., Koob, G. F., & Vale, W. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-05-02579.1994 · Cited by 468 · see citing works
Lee, Y., & Davis, M. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-16-06434.1997 · Cited by 457 · see citing works
Müller, M. B., Zimmermann, S., Sillaber, I., Hagemeyer, T. P., Deussing, J. M., Timpl, P., Kormann, M., Droste, S. K., Kühn, R., Reul, J. M. H. M., et al. (2003) · Nature Neuroscience · doi:10.1038/nn1123 · Cited by 446 · see citing works
Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders
Holmes, A., Heilig, M. A., Rupniak, N. M. J., Steckler, T., & Griebel, G. (2003) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2003.09.011 · Cited by 401 · see citing works
Campeau, S., & Davis, M. (1995) · Journal of Neuroscience · doi:10.1523/jneurosci.15-03-02312.1995 · Cited by 379 · see citing works
Neural circuits mediating stress
López, J. F., Akil, H., & Watson, S. J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00266-8 · Cited by 373 · see citing works
Corticotropin-Releasing Factor in Brain: A Role in Activation, Arousal, and Affect Regulation
Heinrichs, S. C., & Koob, G. F. (2004) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.052092 · Cited by 353 · see citing works
Sakanaka, M., Shibasaki, T., & Lederis, K. (1986) · Brain Research · doi:10.1016/0006-8993(86)91332-6 · Cited by 337 · see citing works
Extended Amygdala and Basal Forebrain
Alheid, G. F. (2003) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2003.tb07082.x · Cited by 334 · see citing works
Stolerman, I. P. (2010) · Springer eBooks · doi:10.1007/978-3-540-68706-1_4410 · Cited by 322 · see citing works
Development of Cushing's syndrome in corticotropin-releasing factor transgenic mice
Stenzel‐Poore, M. P., Cameron, V. A., Vaughan, J. M., Sawchenko, P. E., & Vale, W. (1992) · Endocrinology · doi:10.1210/endo.130.6.1597149 · Cited by 263 · see citing works
Albeck, D. S., McKittrick, C. R., Blanchard, D. C., Blanchard, R. J., Nikulina, J., McEwen, B. S., & Sakai, R. R. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-12-04895.1997 · Cited by 261 · see citing works
Roozendaal, B., Brunson, K. L., Holloway, B. L., McGaugh, J. L., & Baram, T. Z. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.212504599 · Cited by 258 · see citing works
Stress sensitivity and the development of affective disorders
Bale, T. L. (2006) · Hormones and Behavior · doi:10.1016/j.yhbeh.2006.06.033 · Cited by 245 · see citing works
Griebel, G., Simiand, J., Steinberg, R., Jung, M., Gully, D., Roger, P., Geslin, M., Scatton, B., Maffrand, J., & Soubrié, P. (2002) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.301.1.333 · Cited by 238 · see citing works
Corticotropin-releasing factor CRF1, but not CRF2, receptors mediate anxiogenic-like behavior
Heinrichs, S. C., Lapsansky, J., Lovenberg, T. W., Souza, E. B. D., & Chalmers, D. T. (1997) · Regulatory Peptides · doi:10.1016/s0167-0115(97)01005-7 · Cited by 235 · see citing works
Herman, J. P., Cullinan, W. E., & Watson, S. J. (1994) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.1994.tb00604.x · Cited by 235 · see citing works
Perrault, G., Griebel, G., & Sanger, D. J. (1998) · Psychopharmacology · doi:10.1007/s002130050645 · Cited by 210 · see citing works
Sajdyk, T. J., Schober, D. A., Gehlert, D. R., & Shekhar, A. (1999) · Behavioural Brain Research · doi:10.1016/s0166-4328(98)00132-6 · Cited by 191 · see citing works
The Role of Corticotropin-Releasing Factor in the Pathogenesis of Major Depression
Nemeroff, C. B. (1988) · Pharmacopsychiatry · doi:10.1055/s-2007-1014652 · Cited by 185 · see citing works
The therapeutic potential of CRF1 antagonists for anxiety
Zorrilla, E., & Koob, G. (2004) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.13.7.799 · Cited by 173 · see citing works
Kim, M., Campeau, S., Falls, W. A., & Davis, M. (1993) · Behavioral and Neural Biology · doi:10.1016/0163-1047(93)91075-x · Cited by 164 · see citing works
Fear-potentiated startle using an auditory conditioned stimulus: Effect of lesions of the amygdala
Hitchcock, J. M., & Davis, M. (1987) · Physiology & Behavior · doi:10.1016/0031-9384(87)90242-3 · Cited by 158 · see citing works
Viau, V., & Sawchenko, P. E. (2002) · The Journal of Comparative Neurology · doi:10.1002/cne.10178 · Cited by 153 · see citing works
Lu, A., Steiner, M. A., Whittle, N., Vogl, A. M., Walser, S. M., Ableitner, M., Refojo, D., Ekker, M., Rubenstein, J. L. R., Stalla, G. K., et al. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.51 · Cited by 136 · see citing works
New vistas in neuropeptide research in neuropsychiatry: focus on corticotropin-releasing factor.
Nemeroff, C. B. (1992) · PubMed · Cited by 136 · see citing works
Keen‐Rhinehart, E., Michopoulos, V., Toufexis, D. J., Martin, E. I., Nair, H. P., Ressler, K. J., Davis, M., Owens, M. J., Nemeroff, C. B., & Wilson, M. E. (2008) · Molecular Psychiatry · doi:10.1038/mp.2008.91 · Cited by 126 · see citing works
HPA axis dysregulation in mice overexpressing corticotropin releasing hormone
Groenink, L., Dirks, A., Verdouw, P. M., Schipholt, M. L., Veening, J. G., van der Gugten, J., & Olivier, B. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01334-3 · Cited by 126 · see citing works
Sensitivity to stress: Dysregulation of CRF pathways and disease development
Bale, T. L. (2005) · Hormones and Behavior · doi:10.1016/j.yhbeh.2005.01.009 · Cited by 122 · see citing works
Arborelius, L., Skelton, K. H., Thrivikraman, K. V., Plotsky, P. M., Schulz, D. W., & Owens, M. J. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)39110-4 · Cited by 101 · see citing works
Stout, S. C., Mortas, P., Owens, M. J., Nemeroff, C. B., & Moreau, J.-L. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(00)00412-x · Cited by 94 · see citing works
Chen, A., Zorrilla, E. P., Smith, S., Rousso, D. L., Levy, C. L., Vaughan, J. M., Donaldson, C., Roberts, A. L., Lee, K., & Vale, W. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.3955-05.2006 · Cited by 91 · see citing works
Self-citationDirks, A., Groenink, L., Bouwknecht, J. A., Hijzen, T. H., van der Gugten, J., Ronken, E., Verbeek, J. S., Veening, J. G., Dederen, P. J. W. C., Kőrösi, A., et al. (2002) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2002.02245.x · Cited by 91 · see citing works
Brunson, K. L., Grigoriadis, D. E., Lorang, M. T., & Baram, T. Z. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7937 · Cited by 74 · see citing works
Distribution and expression of CRF receptor 1 and 2 mRNAs in the CRF over-expressing mouse brain
Kőrösi, A., Veening, J. G., Kozicz, T., Henckens, M. J. A. G., Dederen, J., Groenink, L., van der Gugten, J., Olivier, B., & Roubos, E. W. (2006) · Brain Research · doi:10.1016/j.brainres.2005.12.034 · Cited by 72 · see citing works
Oakley, R. H., Olivares-Reyes, J. A., Hudson, C. C., Flores-Vega, F., Dautzenberg, F. M., & Hauger, R. L. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00099.2006 · Cited by 67 · see citing works
Iredale, P. A., Terwilliger, R. Z., Widnell, K. L., Nestler, E. J., & Duman, R. S. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09538-0 · Cited by 67 · see citing works
Perry, S. J., Junger, S., Kohout, T. A., Hoare, S. R. J., Struthers, R. S., Grigoriadis, D. E., & Maki, R. A. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412914200 · Cited by 60 · see citing works
Herringa, R. J., Nanda, S. A., Hsu, D. T., Roseboom, P. H., & Kalin, N. H. (2004) · Molecular Brain Research · doi:10.1016/j.molbrainres.2004.08.005 · Cited by 55 · see citing works
Kim, S.-J., Park, S.-H., Choi, S.-H., Moon, B., Lee, K. J., Kang, S., Lee, M.-S., Choi, S.-H., Chun, B., & Shin, K.-H. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2005.12.003 · Cited by 48 · see citing works
Rasmussen, T. N., Novak, I., & Nielsen, S. M. (2004) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.2004.04371.x · Cited by 40 · see citing works
CRF1 Not Glucocorticoid Receptors Mediate Prepulse Inhibition Deficits in Mice Overexpressing CRF
Groenink, L., Dirks, A., Verdouw, P. M., de Graaff, M., Peeters, B. W. M. M., Millan, M. J., & Olivier, B. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.06.002 · Cited by 33 · see citing works
A Common Genetic Predisposition to Stress Sensitivity and Stress-Induced Nicotine Craving
Bilkei‐Gorzó, A., Rácz, I., Michel, K., Darvas, M., Maldonado, R., & Zimmer, A. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.02.010 · Cited by 29 · see citing works
Herringa, R. J., Mackenrodt, D. B., Barlow, J. D., Roseboom, P. H., Nanda, S. A., & Kalin, N. H. (2006) · Brain Research · doi:10.1016/j.brainres.2006.01.122 · Cited by 9 · see citing works
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Self-citationSterrenburg, L., Gaszner, B., Boerrigter, J., Santbergen, L., Bramini, M., Elliott, E., Chen, A., Peeters, B. W. M. M., Roubos, E. W., & Kozicz, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028128 · Cited by 149 · see citing works
Self-citationHammack, S. E., Cooper, M. A., & Lezak, K. R. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.02.024 · Cited by 142 · see citing works
Maras, P. M., Molet, J., Chen, Y., Rice, C., Ji, S. G., Solodkin, A., & Baram, T. Z. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.12 · Cited by 118 · see citing works
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Regev, L., Tsoory, M., Gil, S., & Chen, A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.036 · Cited by 93 · see citing works
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Oler, J. A., Birn, R. M., Patriat, R., Fox, A. S., Shelton, S. E., Burghy, C. A., Stodola, D. E., Essex, M. J., Davidson, R. J., & Kalin, N. H. (2012) · NeuroImage · doi:10.1016/j.neuroimage.2012.03.045 · Cited by 67 · see citing works
- Authors
- Regev, L., Neufeld-Cohen, A., Tsoory, M., Kuperman, Y., Getselter, D., Gil, S., & Chen, A.
- Affiliations
- Weizmann Institute of Science (IL)
- Corresponding author
- Chen, A
- Venue
- Molecular Psychiatry
- Published
- 2010-06-15
- Volume
- 16
- Issue
- 7
- Pages
- 714-728
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W1985387196
- Cited by
- 110
- References
- 71
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 6 · 2017: 7 · 2016: 14 · 2015: 6 · 2014: 10 · 2013: 11 · 2012: 13
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- corticotropin-releasing factor, extended amygdala, central amygdala, bed nucleus of the stria terminalis, chronic stress, anxiety-like behavior, depression-like behavior, lentiviral overexpression, stress response, emotion regulation
- MeSH terms
- CRF Receptor, Type 1, Adaptation, Physiological, Amygdala, Animals, Anxiety, Behavior, Animal, Cell Line, Transformed, Corticotropin-Releasing Hormone, Disease Models, Animal, Exploratory Behavior, Genetic Vectors, Humans, Male, Mice, Inbred C57BL, RNA, Messenger, Reflex, Startle, Stress, Psychological, Time Factors, Transduction, Genetic, Transfection, Lentivirus, Receptors, Corticotropin-Releasing Hormone, Green Fluorescent Proteins, Mice
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