Cited by 81Bipolar Disorder and TreatmentNeurotransmitter Receptor Influence on BehaviorCircadian rhythm and melatonin

Mice with reduced DAT levels recreate seasonal-induced switching between states in bipolar disorder

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Young, Jared W., Cope, Zackary A., Romoli, Benedetto, Schrurs, Esther, Aniek Joosen, van Enkhuizen, Jordy, Sharp, Richard F., Dulcis, Davide·2018·Neuropsychopharmacology

Abstract

Developing novel therapeutics for bipolar disorder (BD) has been hampered by limited mechanistic knowledge how sufferers switch between mania and depression-how the same brain can switch between extreme states-described as the "holy grail" of BD research. Strong evidence implicates seasonally-induced switching between states, with mania associated with summer-onset, depression with winter-onset. Determining mechanisms of and sensitivity to such switching is required. C57BL/6J and dopamine transporter hypomorphic (DAT-HY 50% expression) mice performed a battery of psychiatry-relevant behavioral tasks following 2-week housing in chambers under seasonally relevant photoperiod extremes. Summer-like and winter-like photoperiod exposure induced mania-relevant and depression-relevant behaviors respectively in mice. This behavioral switch paralleled neurotransmitter switching from dopamine to somatostatin in hypothalamic neurons (receiving direct input from the photoperiod-processing center, the suprachiasmatic nucleus). Mice with reduced DAT expression exhibited hypersensitivity to these summer-like and winter-like photoperiods, including more extreme mania-relevant (including reward sensitivity during reinforcement learning), and depression-relevant (including punishment-sensitivity and loss-sensitivity during reinforcement learning) behaviors. DAT mRNA levels switched in wildtype littermate mice across photoperiods, an effect not replicated in DAT hypomorphic mice. This inability to adjust DAT levels to match photoperiod-induced neurotransmitter switching as a homeostatic control likely contributes to the susceptibility of DAT hypormophic mice to these switching photoperiods. These data reveal the potential contribution of photoperiod-induced neuroplasticity within an identified circuit of the hypothalamus, linked with reduced DAT function, underlying switching between states in BD. Further investigations of the circuit will likely identify novel therapeutic targets to block switching between states.

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  • A recent study proposed a mouse model of state switching based on photoperiod wherein mice with reduced dopamine transporter (DAT) expression differentially express increased depressive-like or mania-like behaviors dependent upon day length.

    “A recent study proposed a mouse model of state switching based on photoperiod wherein it was reported that mice with reduced dopamine transporter (DAT) expression differentially express increased depressive-like or mania-like behaviors dependent upon day length134.”

    From Circadian rhythm disruption and mental health (2020) · cites this paper as [134]

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  1. Greenwood TA, Alexander M, Keck PE, McElroy S, Sadovnick AD, Remick RA, et al. Evidence for linkage disequilibrium between the dopamine transporter and bipolar disorder. Am J Med Genet. 2001;105:145-51.

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Authors
Young, J. W., Cope, Z. A., Romoli, B., Schrurs, E., Joosen, A., van Enkhuizen, J., Sharp, R. F., & Dulcis, D.
Affiliations
  • University of California San Diego (US)
  • Utrecht University (NL)
Corresponding author
  • Young, Jared W.
  • Dulcis, Davide
Venue
Neuropsychopharmacology
Published
2018-02-27
Volume
43
Issue
8
Pages
1721-1731
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
OpenAlex
W2793654854
Cited by
81
References
60
Citations by year
2026: 1 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 29 · 2020: 11 · 2019: 8 · 2018: 3
FWCI
10.00
Type
journal article
Language
en
Open access
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • University of California, San Diego
  • National Institute of Mental Health (R01MH104344, T32MH018399)
  • NIH Clinical Center
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 › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords
bipolar disorder, mania, depression, dopamine transporter, photoperiod, hypothalamus, somatostatin, suprachiasmatic nucleus, neuroplasticity, reward sensitivity, punishment sensitivity, loss sensitivity, reinforcement learning
MeSH terms
Animals, Behavior, Animal, Bipolar Disorder, Disease Models, Animal, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Paraventricular Hypothalamic Nucleus, Reward, Risk-Taking, RNA, Messenger, Seasons, Photoperiod, Dopamine Plasma Membrane Transport Proteins, CLOCK Proteins

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