An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors
Open accessAbstract
Mice with a mutation in the Clock gene (ClockΔ19) have been identified as a model of mania; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium's effectiveness on these mice remain unclear. Here, we find that cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockΔ19 mice. Selective knockdown of Cck expression via RNA interference in the VTA of wild-type mice produces a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild-type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockΔ19 mice appears to be due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. Human postmortem tissue from bipolar subjects reveals a similar increase in Cck expression in the VTA with mood stabilizer treatment. These studies identify a key role for Cck in the development and treatment of mania, and describe some of the molecular mechanisms by which lithium may act as an effective antimanic agent.
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Clock regulates cholecystokinin (CCK) expression in the ventral tegmental area (VTA), and the Δ19 mutation in the Clock gene is sufficient to induce manic-like behaviors.
“Notably, clock regulates cholecystokinin (CCK) expression in the ventral tegmental area (VTA) and Δ19 mutation in the Clock gene is sufficient to induce manic-like behaviors102.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [102]
Circadian genes in brain regions outside the SCN contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and disruption of these functions might contribute to brain disorders.
“circadian genes in other brain regions outside of this central pace-maker also contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and the disruption of these functions might contribute to brain disorders264,304–315”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [304]
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Cites
The diverse functions of histone lysine methylation
Martin, C., & Zhang, Y. (2005) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1761 · Cited by 2,066 · see citing works
Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action
Tsankova, N. M., Berton, O., Renthal, W., Kumar, A., Neve, R. L., & Nestler, E. J. (2006) · Nature Neuroscience · doi:10.1038/nn1659 · Cited by 1,780 · see citing works
Molecular components of the mammalian circadian clock
Ko, C. H., & Takahashi, J. S. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl207 · Cited by 1,657 · see citing works
Mutagenesis and Mapping of a Mouse Gene, <i>Clock</i> , Essential for Circadian Behavior
Vitaterna, M. H., King, D. P., Chang, A.-M., Kornhauser, J. M., Lowrey, P. L., McDonald, J. D., Dove, W. F., Pinto, L. H., Turek, F. W., & Takahashi, J. S. (1994) · Science · doi:10.1126/science.8171325 · Cited by 1,632 · see citing works
Circadian Regulator CLOCK Is a Histone Acetyltransferase
Doi, M., Hirayama, J., & Sassone‐Corsi, P. (2006) · Cell · doi:10.1016/j.cell.2006.03.033 · Cited by 890 · see citing works
Mania-like behavior induced by disruption of <i>CLOCK</i>
Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0609625104 · Cited by 803 · see citing works
Self-citationEvidence for coexistence of dopamine and CCK in meso-limbic neurones
Hökfelt, T. G. M., Rehfeld, J. F., Skirboll, L. R., IVEMARK, B. I., Goldstein, M., & MARKEY, K. (1980) · Nature · doi:10.1038/285476a0 · Cited by 707 · see citing works
Circadian genes, rhythms and the biology of mood disorders
McClung, C. A. (2007) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2007.02.003 · Cited by 666 · see citing works
Self-citationHughes, J. W., Boden, P., Costall, B., Domeney, A. M., Kelly, E., Horwell, D. C., Hunter, J. C., Pinnock, R. D., & Woodruff, G. N. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.17.6728 · Cited by 501 · see citing works
Regulation of dopaminergic transmission and cocaine reward by the <i>Clock</i> gene
McClung, C. A., Sidiropoulou, K., Vitaterna, M., Takahashi, J. S., White, F. J., Cooper, D. C., & Nestler, E. J. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0503584102 · Cited by 493 · see citing works
Self-citationTsankova, N. M., Kumar, A., & Nestler, E. J. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.0589-04.2004 · Cited by 447 · see citing works
Human postmortem tissue: What quality markers matter?
Stan, A. D., Ghose, S., Gao, X.-M., Roberts, R. C., Lewis-Amezcua, K., Hatanpaa, K. J., & Tamminga, C. A. (2006) · Brain Research · doi:10.1016/j.brainres.2006.09.025 · Cited by 361 · see citing works
Self-citationSoria, V., Martínez‐Amorós, È., Escaramís, G., Valero, J., Pérez‐Egea, R., García, C. B., Gutiérrez‐Zotes, A., Puigdemont, D., Bayés, M., Crespo, J. M., et al. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.230 · Cited by 352 · see citing works
Nievergelt, C. M., Kripke, D. F., Barrett, T. B., Burg, E., Remick, R. A., Sadovnick, A. D., McElroy, S. L., Keck, P. E., Schork, N. J., & Kelsoe, J. R. (2006) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30252 · Cited by 294 · see citing works
Mansour, H. A., Wood, J., Logue, T., Chowdari, K. V., Dayal, M., Kupfer, D. J., Monk, T. H., Devlin, B., & Nimgaonkar, V. L. (2006) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00147.x · Cited by 293 · see citing works
The histone methyltransferase MLL1 permits the oscillation of circadian gene expression
Katada, S., & Sassone‐Corsi, P. (2010) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.1961 · Cited by 291 · see citing works
Serretti, A., Benedetti, F., Mandelli, L., Lorenzi, C., Pirovano, A., Colombo, C., & Smeraldi, E. (2003) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.20053 · Cited by 264 · see citing works
Mukherjee, S., Coque, L., Cao, J., Kumar, J., Chakravarty, S., Asaithamby, A., Graham, A., Gordon, E., Enwright, J. F., Dileone, R., et al. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.04.031 · Cited by 249 · see citing works
Self-citationSleep and circadian functioning: critical mechanisms in the mood disorders?
Harvey, A. G. (2011) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-032210-104550 · Cited by 237 · see citing works
Circadian polymorphisms associated with affective disorders
Kripke, D. F., Nievergelt, C. M., Joo, E., Shekhtman, T., & Kelsoe, J. R. (2009) · Journal of Circadian Rhythms · doi:10.1186/1740-3391-7-2 · Cited by 225 · see citing works
The role of circadian clock genes in mental disorders
Lamont, E. W., Coutu, D. L., Cermakian, N., & Boivin, D. B. (2007) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2007.9.3/elamont · Cited by 224 · see citing works
Behavioral effects of neuropeptides in rodent models of depression and anxiety
Rotzinger, S., Lovejoy, D. A., & Tan, L. A. (2010) · Peptides · doi:10.1016/j.peptides.2009.12.015 · Cited by 211 · see citing works
Benedetti, F., Dallaspezia, S., Fulgosi, M. C., Lorenzi, C., Serretti, A., Barbini, B., Colombo, C., & Smeraldi, E. (2007) · American Journal of Medical Genetics Part B Neuropsychiatric Genetics · doi:10.1002/ajmg.b.30475 · Cited by 205 · see citing works
H3 Lysine 4 Is Acetylated at Active Gene Promoters and Is Regulated by H3 Lysine 4 Methylation
Guillemette, B., Drogaris, P., Lin, H.-H. S., Armstrong, H., Hiragami-Hamada, K., Imhof, A., Bonneil, É., Thibault, P., Verreault, A., & Festenstein, R. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001354 · Cited by 199 · see citing works
Cross-talk between Histone Modifications in Response to Histone Deacetylase Inhibitors
Nightingale, K. P., Gendreizig, S., White, D. A., Bradbury, C. A., Hollfelder, F., & Turner, B. M. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m606773200 · Cited by 192 · see citing works
The Mouse Clock Mutation Behaves as an Antimorph and Maps Within the W19H Deletion, Distal of Kit
King, D. P., Vitaterna, M. H., Chang, A., Dove, W. F., Pinto, L. H., Turek, F. W., & Takahashi, J. S. (1997) · Genetics · doi:10.1093/genetics/146.3.1049 · Cited by 162 · see citing works
Mansour, H. A., Talkowski, M. E., Wood, J., Chowdari, K. V., McClain, L., Prasad, K., Montrose, D., Fagiolini, A., Friedman, E. S., Allen, M. H., et al. (2009) · Bipolar Disorders · doi:10.1111/j.1399-5618.2009.00756.x · Cited by 161 · see citing works
Mutagenesis and mapping of a mouse gene, Clock, essential for circadian …
Vitaterna, M. H. (1994) · Science · Cited by 144 · see citing works
Coque, L., Mukherjee, S., Cao, J.-L., Spencer, S., Marvin, M., Falcon, E., Sidor, M. M., Birnbaum, S. G., Graham, A., Neve, R. L., et al. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.33 · Cited by 120 · see citing works
Self-citationCrump, N., Hazzalin, C. A., Bowers, E. M., Alani, R., Cole, P., & Mahadevan, L. C. (2011) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1100099108 · Cited by 104 · see citing works
Circadian rhythms and clock genes in psychotic disorders.
Lamont, E. W., Coutu, D. L., Cermakian, N., & Boivin, D. B. (2010) · PubMed · Cited by 102 · see citing works
Circadian patterns of neurotransmitter related gene expression in motor regions of the rat brain
Weber, M., Lauterburg, T., Tobler, I., & Burgunder, J. ‐. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2003.12.053 · Cited by 94 · see citing works
In vivo release of dopamine in the nucleus accumbens of the rat: modulation by cholecystokinin
Voigt, M. M., & Wang, R. Y. (1984) · Brain Research · doi:10.1016/0006-8993(84)90531-6 · Cited by 87 · see citing works
CIPC is a mammalian circadian clock protein without invertebrate homologues
Zhao, W., Malinin, N. L., Yang, F., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1539 · Cited by 85 · see citing works
Behavioral and neurochemical effects of sodium butyrate in an animal model of mania
Moretti, M., Valvassori, S. S., Varela, R. B., Ferreira, C. L., Rochi, N., Benedet, J., Scaini, G., Kapczinski, F., Streck, E. L., Zugno, A. I., et al. (2011) · Behavioural Pharmacology · doi:10.1097/fbp.0b013e32834d0f1b · Cited by 84 · see citing works
CRY2 Is Associated with Rapid Cycling in Bipolar Disorder Patients
Sjöholm, L. K., Backlund, L., Cheteh, E. H., Ek, I. R., Frisén, L., Schalling, M., Ösby, U., Lavebratt, C., & Nikamo, P. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012632 · Cited by 80 · see citing works
Lithium: Updated Human Knowledge Using an Evidence-Based Approach
Grandjean, E. M., & Aubry, J. (2009) · CNS Drugs · doi:10.2165/00023210-200923030-00004 · Cited by 79 · see citing works
Is Lithium in a Class of Its Own? A Brief Profile of Its Clinical Use
Malhi, G. S., Adams, D., & Berk, M. (2009) · Australian & New Zealand Journal of Psychiatry · doi:10.3109/00048670903279937 · Cited by 62 · see citing works
Schade, R., Vick, K., Ott, T., Sohr, R., Pfister, C., Bellach, J., Golor, G., & Lemmer, B. (1995) · Chronobiology International · doi:10.3109/07420529509064504 · Cited by 56 · see citing works
Hernando, F., Fuentes, J., Roques, B. P., & Ruiz‐Gayo, M. (1994) · European Journal of Pharmacology · doi:10.1016/0014-2999(94)90115-5 · Cited by 55 · see citing works
Cholecystokinergic Innervation of Nucleus Accumbens Subregions
Lança, A. J., de Cabo, C., Arifuzzaman, A. I., et al. (1998) · Peptides · doi:10.1016/s0196-9781(98)00032-1 · Cited by 45 · see citing works
Cholecystokinin gene transcription: promoter elements, transcription factors and signaling pathways
Hansen, T. V. O. (2001) · Peptides · doi:10.1016/s0196-9781(01)00443-0 · Cited by 37 · see citing works
Ghose, S., Crook, J. M., Bartus, C. L., Sherman, T. G., Herman, M. M., Hyde, T. M., Kleinman, J. E., & Akil, M. (2008) · International Journal of Neuroscience · doi:10.1080/00207450802330702 · Cited by 36 · see citing works
Self-citationRegulation of cholecystokinin release from central nerve terminals
Ghijsen, W. E. J. M., Leenders, A. G. M., & Wiegant, V. M. (2001) · Peptides · doi:10.1016/s0196-9781(01)00444-2 · Cited by 29 · see citing works
Cholecystokinin increases intracellular Ca2+ concentration in cultured striatal neurons
Miyoshi, R., Kito, S., & Nomoto, T. (1991) · Neuropeptides · doi:10.1016/0143-4179(91)90102-o · Cited by 26 · see citing works
Kupfer, D. J., Angst, J., Berk, M., Dickerson, F., Frangou, S., Frank, E., Goldstein, B. I., Harvey, A. G., Laghrissi‐Thode, F., Leboyer, M., et al. (2011) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2011.06336.x · Cited by 16 · see citing works
ΔFosB indirectly regulates Cck promoter activity
Enwright, J. F., Wald, M., Paddock, M., Hoffman, E., Arey, R. N., Edwards, S., Spencer, S. M., Nestler, E. J., & McClung, C. A. (2010) · Brain Research · doi:10.1016/j.brainres.2010.02.081 · Cited by 4 · see citing works
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Walker, W. H., Walton, J. C., DeVries, A. C., & Nelson, R. J. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-0694-0 · Cited by 1,030 · see citing works
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Logan, R. W., & McClung, C. A. (2019) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0088-y · Cited by 713 · see citing works
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McClung, C. A. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.02.019 · Cited by 507 · see citing works
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“Frontiers in Molecular Neuroscience | www.frontiersin.org 4 November 2017 | Volume 10 | Article 360 experimenter, location, apparatus and test, et cetera (Wahlsten et al., 2006; Roybal et al., 2007; Mukherjee et al., 2010 Coque et al., 2011; Arey et al., 2013; Spencer et al., 2013).”
BackgroundSelf-citation
- Authors
- Arey, R. N., Enwright, J. F., Spencer, S. M., Falcon, E., Ozburn, A. R., Ghose, S., Tamminga, C., & McClung, C. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Austin College (US)
- University of Pittsburgh (US)
- Corresponding author
- McClung, C A
- Venue
- Molecular Psychiatry
- Published
- 2013-02-12
- Volume
- 19
- Issue
- 3
- Pages
- 342-350
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3783638
- OpenAlex
- W1972216680
- Cited by
- 62
- References
- 47
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 4 · 2020: 7 · 2018: 9 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 1 · 2013: 7
- FWCI
- 4.74
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-04-09)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- McKnight Endowment Fund for Neuroscience
- Brain and Behavior Research Foundation
- Brain Research Foundation
- National Institute on Alcohol Abuse and Alcoholism (F32AA020452)
- National Institute of Mental Health (P50MH096890, R01MH082876, MH082876, F31MH090683)
- National Institute on Drug Abuse (R01DA023988)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- cholecystokinin, clock genes, mania, manic-like behavior, lithium, ventral tegmental area, MLL1, histone H3K4me3, circadian clock, bipolar disorder, mood stabilizers, gene transcription, postmortem brain
- MeSH terms
- Animals, Behavior, Animal, Bipolar Disorder, Cholecystokinin, Humans, Male, Mutation, Histone-Lysine N-Methyltransferase, Ventral Tegmental Area, Lithium Chloride, Mice, Myeloid-Lymphoid Leukemia Protein, Gene Knockdown Techniques, CLOCK Proteins
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