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ABSTRACT: It has been suggested for some time that circadian rhythm abnormalities underlie the development of multiple psychiatric disorders. However, it is unclear how disruptions in individual circadian genes might regulate mood and anxiety. Here we found that mice lacking functional mPeriod 1 (mPer1) or mPeriod 2 (mPer2) individually did not have consistent behavioral abnormalities in measures of anxiety-related behavior. However, mice deficient in both mPer1 and mPer2 had an increase in levels of anxiety-like behavior in multiple measures. Moreover, we found that mPer1 and mPer2 expression was reduced in the nucleus accumbens (NAc) after exposure to chronic social defeat stress, a paradigm that led to increased anxiety-related behavior. Following social defeat, chronic treatment with fluoxetine normalized Per gene expression towards wild-type levels. Knockdown of both mPer1 and mPer2 expression via RNA interference specifically in the NAc led to a similar increase in anxiety-like behavior as seen in the mutant animals. Taken together, these results implicate the Per genes in the NAc in response to stress and the development of anxiety.
European Journal of Neuroscience 10/2012; · 3.63 Impact Factor
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ABSTRACT: Mice with a mutation in the Clock gene (ClockΔ19) have a number of behavioral phenotypes that suggest alterations in dopaminergic transmission. These include hyperactivity, increased exploratory behavior, and increased reward value for drugs of abuse. However, the complex changes in dopaminergic transmission that underlie the behavioral abnormalities in these mice remain unclear. Here we find that a loss of CLOCK function increases dopamine release and turnover in striatum as indicated by increased levels of metabolites HVA and DOPAC, and enhances sensitivity to dopamine receptor antagonists. Interestingly, this enlarged dopaminergic tone results in downstream changes in dopamine receptor (DR) levels with a surprising augmentation of both D1- and D2-type DR protein, but a significant shift in the ratio of D1 : D2 receptors in favor of D2 receptor signaling. These effects have functional consequences for both behavior and intracellular signaling, with alterations in locomotor responses to both D1-type and D2-type specific agonists and a blunted response to cAMP activation in the ClockΔ19 mutants. Taken together, these studies further elucidate the abnormalities in dopaminergic transmission that underlie mood, activity, and addictive behaviors.
Journal of Neurochemistry 07/2012; 123(1):124-34. · 4.06 Impact Factor
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Laurent Coque,
Shibani Mukherjee,
Jun-Li Cao, Sade Spencer,
Marian Marvin,
Edgardo Falcon,
Michelle M Sidor,
Shari G Birnbaum,
Ami Graham,
Rachael L Neve,
Elizabeth Gordon,
Angela R Ozburn,
Matthew S Goldberg,
Ming-Hu Han,
Donald C Cooper,
Colleen A McClung
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ABSTRACT: 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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2011; 36(7):1478-88. · 6.99 Impact Factor
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ABSTRACT: Some of the important biochemical, structural, and behavioral changes induced by chronic exposure to drugs of abuse appear to be mediated by the highly stable transcription factor DeltaFosB. Previous work has shown that DeltaFosB overexpression in mice for 2weeks leads to an increase in the expression of numerous genes in striatum, most of which are later downregulated following 8weeks of FosB expression. Interestingly, a large number of these genes were also upregulated in mice overexpressing the transcription factor CREB. It was unclear from this study, however, whether short-term DeltaFosB regulates these genes via CREB. Here, we find that 2weeks of DeltaFosB overexpression increases CREB expression in striatum, an effect that dissipates by 8weeks. The early induction is associated with increased CREB binding to certain target gene promoters in this brain region. Surprisingly, one gene that was a suspected CREB target based on previous reports, cholecystokinin (Cck), was not controlled by CREB in striatum. To further investigate the regulation of Cck following DeltaFosB overexpression, we confirmed that short-term DeltaFosB overexpression increases both Cck promoter activity and gene expression. It also increases binding activity at a putative CREB binding site (CRE) in the Cck promoter. However, while the CRE site is necessary for normal basal expression of Cck, it is not required for DeltaFosB induction of Cck. Taken together, these results suggest that while short-term DeltaFosB induction increases CREB expression and activity at certain gene promoters, this is not the only mechanism by which genes are upregulated under these conditions.
Brain research 03/2010; 1329:10-20. · 2.46 Impact Factor
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Elizabeth M Cameron, Sade Spencer,
Jonathan Lazarini,
Christopher T Harp,
E Sally Ward,
Mark Burgoon,
Gregory P Owens,
Michael K Racke,
Jeffrey L Bennett,
Elliot M Frohman,
Nancy L Monson
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ABSTRACT: We identified a unique antibody gene mutation pattern (i.e. "signature") in cerebrospinal fluid (CSF) B cells from multiple sclerosis (MS) patients not present in control populations. Prevalence of the signature in CSF B cells of patients at risk to develop MS predicted conversion to MS with 91% accuracy in a small cohort of clinically isolated syndrome patients. If confirmed, signature prevalence would be a novel genetic diagnostic tool candidate for patients with early demyelinating disease of the central nervous system.
Journal of neuroimmunology 08/2009; 213(1-2):123-30. · 2.84 Impact Factor
