Mania-like behavior induced by disruption of CLOCK
Open accessAbstract
Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.
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The ClockΔ19 mutant mouse, a well-established model of bipolar mania, has a fundamentally disrupted molecular circadian clock, and restoration of a functional molecular circadian clock to the VTA ameliorates the mania-like behaviors.
“One of the most well-established models of bipolar mania, the ClockΔ19 mutant mouse, has a fundamentally disrupted molecular circadian clock and restoration of a functional molecular circadian clock to the VTA, likely restoring dopaminergic regulation, ameliorates the mania-like behaviors101.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [101]
The Results (page not available) describe a dominant-negative Clock mutation and report that expressing functional CLOCK protein in the VTA normalized hyperactivity and brought anxiety near wild-type levels. The Discussion calls the mice a bona fide model of human mania. The paper does not show that gene transfer restored a functional molecular circadian clock in the VTA; it tested CLOCK expression and those behavioral outcomes. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMice with a Δ19 mutation in the Clock gene display reduced anxiety-like behavior and are less fearful of aversive stimuli than wild-type mice.
“Mice with a Δ19 mutation in the Clock gene display reduced anxiety-like behavior and are less fearful of aversive stimuli than wild-type mice101.”
From Circadian rhythm disruption and mental health (2020) · cites this paper as [101]
Mice harbouring a mutation in Clock display a behavioural repertoire similar to human mania, and CLOCK specifically in the ventral tegmental area is important for these behaviours via modulation of dopamine cell firing.
“This study demonstrates mice harbouring a mutation in Clock display a behavioural repertoire similar to human mania and provides evidence for CLOCK specifically in the ventral tegmental area to be important for these behaviours via modulation of dopamine cell firing.”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [313]
Disruption of one of the core proteins in the master circadian clock can trigger mania-like behaviors.
“Recent studies show that disruption of one of the core proteins in the master circadian clock can trigger mania-like behaviors (Roybal et al., 2007)”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Roybal et al., 2007
Mice with a mutation in the Clock gene have a behavioral profile that is strikingly similar to human mania.
“Mice with a mutation in the Clock gene have a behavioral profile that is strikingly similar to human mania (McClung et al., 2005; Roybal et al., 2007).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Roybal et al., 2007
The manic-like profile of Clock mutant mice includes hyperactivity, lowered depression-like behavior, greater risk taking behavior, an increase in the preference for sucrose and cocaine, and an increase in goal-directed behavior resulting in intracranial self-stimulation.
“This includes hyperactivity, lowered depression-like behavior, greater risk taking behavior, an increase in the preference for sucrose and cocaine, and an increase in goal-directed behavior resulting in intracranial self-stimulation.”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Roybal et al., 2007
Viral-mediated gene transfer to place a functional Clock gene back into the VTA of Clock mutant mice rescued their hyperactivity and anxiety-related behavioral abnormalities.
“viral-mediated gene transfer was used to place a functional Clock gene back into the VTA of the Clock mutant mice. This was able to rescue their hyperactivity and anxiety-related behavioral abnormalities (Roybal et al., 2007).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Roybal et al., 2007
The majority of these phenotypes are reversed when animals are treated chronically with the mood stabilizer, lithium.
“Furthermore, the majority of these phenotypes are reversed when animals are treated chronically with the mood stabilizer, lithium (Roybal et al., 2007).”
From Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges (2009) · cites this paper as Roybal et al., 2007
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Self-citationA role for the circadian genes in drug addiction
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Self-citationBiological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges
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Self-citationThe circadian system of patients with bipolar disorder differs in episodes of mania and depression
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Self-citationAssessment of circadian function in fibroblasts of patients with bipolar disorder
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Self-citationDirect Regulation of Diurnal Drd3 Expression and Cocaine Reward by NPAS2
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Self-citationSleep- and circadian rhythm–associated pathways as therapeutic targets in bipolar disorder
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Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction
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Self-citationTranslational research in bipolar disorder: emerging insights from genetically based models
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Lithium Ameliorates Nucleus Accumbens Phase-Signaling Dysfunction in a Genetic Mouse Model of Mania
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Self-citationMinutes, days and years: molecular interactions among different scales of biological timing
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Cocaine self-administration behaviors in ClockΔ19 mice
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Self-citationPER2 rs2304672 polymorphism moderates circadian-relevant reward circuitry activity in adolescents
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Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder
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Sleep and dreaming are for important matters
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“Circadian (Wirz-Justice, 2003; Roybal et al., 2007; Li et al., 2013) and neuroendocrine (Schmider et al., 1995; Spiegel et al., 1999; Holsboer, 2000) mechanisms may partially, but not totally subserve a direct causality between sleep disturbances and mood disorders.”
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Reverse translational strategies for developing animal models of bipolar disorder
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Ketamine Influences CLOCK:BMAL1 Function Leading to Altered Circadian Gene Expression
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Investigating the mechanism(s) underlying switching between states in bipolar disorder
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Circadian dysregulation in Parkinson's disease
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Self-citationSeasonal changes in mood and behavior are linked to metabolic syndrome
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Role for the<i>Clock</i>Gene in Bipolar Disorder
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Self-citationCerebrospinal fluid sodium rhythms
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NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors
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“This phenotype is similar to that of Clock∆19 mutant mice, which exhibit reduced anxiety-like behaviors and is the opposite of the Per1/Per2 double mutant, which exhibit increased anxiety-like behavior (Roybal et al., 2007; Spencer et al., 2013).”
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Self-citationUtilization of Diurnal Rodents in the Research of Depression
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Circadian Polymorphisms in Night Owls, in Bipolars, and in Non-24-Hour Sleep Cycles
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Photoperiodic suppression of drug reinstatement
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Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat
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Are 24-hour motor activity patterns associated with continued rapid response to ketamine?
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Cognition and mood-related behaviors in L3mbtl1 null mutant mice
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- Authors
- Roybal, K., Theobold, D., Graham, A., DiNieri, J. A., Russo, S. J., Krishnan, V., Chakravarty, S., Peevey, J., Oehrlein, N., Birnbaum, S., Vitaterna, M. H., Orsulak, P., Takahashi, J. S., Nestler, E. J., Carlezon, W. A., & McClung, C. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Harvard University (US)
- RTX (United States) (US)
- Northwestern University (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-04-10
- Volume
- 104
- Issue
- 15
- Pages
- 6406-6411
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1851061
- OpenAlex
- W2059115988
- Cited by
- 803
- References
- 44
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 29 · 2023: 25 · 2022: 31 · 2021: 32 · 2020: 25 · 2019: 31 · 2018: 40 · 2017: 42 · 2016: 54 · 2015: 45 · 2014: 58 · 2013: 62 · 2012: 51
- FWCI
- 22.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- McKnight Foundation
- National Institutes of Health
- National Institute of Mental Health
- National Institute on Drug Abuse
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- clock genes, mania, bipolar disorder, circadian rhythm, Clock mutant mice, hyperactivity, sleep deprivation, depression-like behavior, anxiety, cocaine reward, sucrose reward, medial forebrain bundle stimulation, lithium, mood stabilizers, ventral tegmental area, dopaminergic activity, animal model of mania
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Analysis of Variance, Animals, Behavioral Symptoms, Bipolar Disorder, Circadian Rhythm, Electric Stimulation, Gene Expression Regulation, Immunohistochemistry, Lithium, Locomotion, Mutation, Genetic Therapy, Trans-Activators, Mutagenesis, Ventral Tegmental Area, Gene Transfer Techniques, Lithium Compounds, Glycogen Synthase Kinase 3, Mice, CLOCK Proteins
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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.
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