TY - JOUR
T1 - Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania
AU - Dzirasa, Kafui
AU - Coque, Laurent
AU - Sidor, Michelle M.
AU - Kumar, Sunil
AU - Dancy, Elizabeth A.
AU - Takahashi, Joseph S.
AU - McClung, Colleen A.
AU - Nicolelis, Miguel A L
PY - 2010/12/1
Y1 - 2010/12/1
N2 - 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.
AB - 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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U2 - 10.1523/JNEUROSCI.4289-10.2010
DO - 10.1523/JNEUROSCI.4289-10.2010
M3 - Article
C2 - 21123577
AN - SCOPUS:78649732829
SN - 0270-6474
VL - 30
SP - 16314
EP - 16323
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 48
ER -