Lithium Ameliorates Nucleus Accumbens Phase-Signaling Dysfunction in a Genetic Mouse Model of Mania
Open accessAbstract
Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30–55 Hz) oscillations to delta (1–4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment.Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function.
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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 [306]
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- Authors
- Dzirasa, K., Coque, L., Sidor, M. M., Kumar, S., Dancy, E. A., Takahashi, J. S., McClung, C. A., & Nicolelis, M. A. L.
- Affiliations
- Duke University (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-12-01
- Volume
- 30
- Issue
- 48
- Pages
- 16314-16323
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3165036
- OpenAlex
- W2018602168
- Cited by
- 85
- References
- 48
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 4 · 2023: 3 · 2022: 7 · 2021: 6 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 10 · 2016: 6 · 2015: 7 · 2014: 6 · 2013: 5 · 2012: 7
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute of Mental Health (P50MH060451)
- National Institute on Drug Abuse (R01DA023988)
- National Institute of Neurological Disorders and Stroke (R33NS049534)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- lithium, nucleus accumbens, phase coupling, low gamma oscillations, delta oscillations, clock genes, mania, bipolar disorder, circadian genes, dendritic morphology, GluR1, novel environment exploration, hyperactivity
- MeSH terms
- Animals, Biological Clocks, Bipolar Disorder, Circadian Rhythm, Disease Models, Animal, Lithium, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Nerve Net, Nucleus Accumbens, Signal Transduction, Mice, CLOCK Proteins
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