Specific Role of VTA Dopamine Neuronal Firing Rates and Morphology in the Reversal of Anxiety-Related, but not Depression-Related Behavior in the ClockΔ19 Mouse Model of Mania
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Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockΔ19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockΔ19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockΔ19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockΔ19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockΔ19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.
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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 [305]
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References 36 · Cited by 120
- Authors
- Coque, L., Mukherjee, S., Cao, J.-L., Spencer, S., Marvin, M., Falcon, E., Sidor, M. M., Birnbaum, S. G., Graham, A., Neve, R. L., Gordon, E., Ozburn, A. R., Goldberg, M. S., Han, M.-H., Cooper, D. C., & McClung, C. A.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Colorado Boulder (US)
- Massachusetts Institute of Technology (US)
- Corresponding author
- McClung, Colleen A
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2011-03-23
- Volume
- 36
- Issue
- 7
- Pages
- 1478-1488
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3096816
- OpenAlex
- W2021092225
- Cited by
- 120
- References
- 36
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 10 · 2017: 9 · 2016: 9 · 2015: 9 · 2014: 14 · 2013: 7 · 2012: 4
- FWCI
- 6.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- McKnight Foundation
- National Alliance for Research on Schizophrenia and Depression (NS058339)
- National Institute of Mental Health (R01MH082876)
- National Institute on Drug Abuse (R01DA023988, K01DA017750)
- National Institute of Neurological Disorders and Stroke (R21NS058339)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- mania, bipolar disorder, lithium, ventral tegmental area, dopaminergic neurons, neuronal firing rate, neuronal morphology, nucleus accumbens dopamine, anxiety-like behavior, depression-like behavior, Kir2.1 potassium channel, neuronal excitability, mood stabilization
- MeSH terms
- Action Potentials, Analysis of Variance, Animals, Anxiety, Bipolar Disorder, Cell Count, Chromatography, High Pressure Liquid, Dark Adaptation, Depression, Disease Models, Animal, Dopamine, Helplessness, Learned, Histones, Locomotion, Male, Mice, Inbred BALB C, Mutation, Neurons, Swimming, Tyrosine 3-Monooxygenase, Ventral Tegmental Area, Lithium Chloride, Mice, Knockout, Patch-Clamp Techniques, Maze Learning, Green Fluorescent Proteins, Mice, CLOCK Proteins, In Vitro Techniques
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