Browsing by Subject "Bipolar Disorder"
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Item Identification of Molecular Mechanisms That Underlie the Development and Treatment of Manic-Like Behaviors in Mice: the Importance of Cholecystokinin and Chromatin Modifications(2012-07-09) Arey, Rachel Nicole; McClung, ColleenBipolar disorder (BPD) is a severe and chronic psychiatric disease that is defined by the occurrence of one or more manic or mixed episodes. The underlying cause of BPD, as well as the mechanisms of action of current pharmacological treatments for BPD, are poorly understood. Mice with a mutation in the Clock gene (ClockDelta19) have been identified as a model of mania that respond to lithium treatment; however, the mechanisms that underlie this phenotype, and the changes in the brain that are necessary for lithium’s effectiveness on these mice remain unclear. Here we find that Cholecystokinin (Cck) is a direct transcriptional target of CLOCK and levels of Cck are reduced in the ventral tegmental area (VTA) of ClockDelta19 mice. Selective knock-down of Cck expression via RNA interference (RNAi) in the VTA of wild type mice is sufficient to produce a manic-like phenotype. Moreover, chronic treatment with lithium restores Cck expression to near wild type and this increase is necessary for the therapeutic actions of lithium. The decrease in Cck expression in the ClockDelta19 mice is due to a lack of interaction with the histone methyltransferase, MLL1, resulting in decreased histone H3K4me3 and gene transcription, an effect reversed by lithium. We also found that another mood stabilizer, valproate (VPA), has mood stabilizing effects in the ClockDelta19 mice, and that VPA causes a restoration of Cck levels in the VTA, similar to lithium. Further investigation into the regulation of the Cck gene by VPA identified a role for histone acetylation in the therapeutic actions of mood stabilizers in the ClockDelta19 mice. Both lithium and VPA cause increases in histone acetylation at the Cck promoter, though potentially through different mechanisms. Lithium treatment may cause recruitment of specific chromatin remodeling complexes, while VPA appears to regulate the Cck gene through HDAC inhibition. The importance of HDAC inhibition in VPA’s therapeutic actions was strengthened by the finding that administration of the specific Class I and IIb HDAC inhibitor suberoylanilide hydroxamic acid was sufficient to rescue manic-like behaviors in the ClockDelta19 mice. These studies identify a key role for Cck in the development and treatment of mania, and for regulation of chromatin modifications in the therapeutic actions of mood stabilizers.Item The Impact of Cognition on Treatment Adherence in Comorbid Bipolar Disorder and Cocaine Dependence(2013-01-17) Fagan, Colleen Susan; Brown, E., Sherwood, M.D., Ph.D.Although bipolar disorder and substance dependence are associated with treatment nonadherence and cognitive impairment, few studies have investigated the relationship between treatment adherence and cognitive functioning. Participants in this study were 120 outpatients with bipolar disorder and cocaine dependence enrolled in a 10 week randomized, double-blind, placebo controlled trial of lamotrigine. Baseline performance on the Stroop Color and Word Test and the Rey Auditory Verbal Learning Test were examined for their effect on retention, appointment attendance, medication adherence, and return of medication bottles. Participants with decreased scores on Word condition of the Stroop Color and Word Test were more likely and those with decreased Interference scores were as likely to attend appointments. Participants with better Rey Auditory Verbal Learning Test Total Recall scores returned more medication bottles. Cognitive functioning did not impact medication adherence or study retention. The findings suggest a relationship between cognitive functioning and treatment attendance. Assessment and treatment of cognitive dysfunction may identify and help patients at-risk for treatment nonadherence. Future studies with a more comprehensive neuropsychological test battery and advanced medication adherence measures are warranted.Item The Relationship between Two Endophenotypes of Psychosis in Volunteers with Schizophrenia and Bipolar Disorder(2010-11-02T18:17:53Z) Moates, Amanda Frances; Tamminga, CarolBackground: Deficits in smooth pursuit eye movements are an established endophenotype for schizophrenia (SZ) and are being investigated as a potential biomarker for psychotic bipolar disorder (BDP). While the molecular determinant of the physiological deficit is still unclear, considerable research has shown deficits in the predictive mechanism of eye movements in SZ using target-masking techniques, as well as with a more recent novel prediction eye movement task. The questions of whether this deficit is related to working memory alterations in SZ and extends to other psychotic disorders like BDP were a focus of this investigation. Methods: Volunteers with schizophrenia (SZ, n = 38), bipolar I disorder with psychotic features (BDP, n = 31), and healthy controls (HC, n = 17) performed a novel eye movement task to assess the predictive mechanism of smooth pursuit. Subjects also completed a battery of neuropsychological tasks that included measures of working memory. Results: Individuals with SZ and BDP performed similarly on both neuropsychological and eye tracking tasks. Both groups evidenced reduced predictive pursuit velocity and worse performance on the Wechsler Spatial Span task compared with healthy controls. Further, a small but significant correlation (r = .27, p = .03) between predictive pursuit gain and working memory performance on Spatial Span was obtained, without statistically significant correlations in other cognitive domains. Conclusions: Individuals with SZ and BDP showed similar deficits on the predictive pursuit eye movement task, suggesting that this alteration could be a characteristic of the psychosis domain. The a priori prediction that the predictive pursuit task is associated with working memory mechanisms was supported in part by its significant and selective correlation with a measure of working memory.Item The Role of CLOCK in Regulation of Dopamine Neurotransmission in the CLOCKdelta19 Mutant Mouse Model(2012-07-17) Spencer, Sade Monique; McClung, Colleen A.Mice with a mutation in the circadian gene Clock (Clockdelta19) display a behavioral profile which parallels a euphoric manic-like state including hyperactivity, disrupted activity rhythms, increased substance abuse vulnerability, and decreases in anxiety and depression-related behavior. The molecular clock has significant cross-talk with many of the brain’s neurotransmitter systems. The purpose of this dissertation is to characterize the role of CLOCK in regulating dopamine transmission in mood and reward-related circuits. We present a mechanism by which CLOCK regulates dopaminergic activity in the mesoaccumbens circuit and contributes to anxiety-related behavior. In vivo recording of ventral tegmental area (VTA) dopamine cells throughout the 24 hour cycle revealed that firing and bursting was elevated in Clockdelta19 mutants with the most significant deviations early in the light cycle. Mimicking this increase in dopaminergic activity using optogenetic targeting resulted in decreased anxiety-related behavior similar to the Clockdelta19 phenotype. Consistent with the electrophysiological findings, tyrosine hydroxylase (TH) mRNA and protein was elevated in the VTA in a daytime-specific manner leading to increased dopamine synthesis in the nucleus accumbens. CLOCK binding was detected at E-box elements within the TH promoter with greater enrichment observed during the light phase when TH expression is low. These results suggest a negative regulation of TH by CLOCK. To examine alterations in the nigrostriatal dopamine circuit, HPLC measurements of dopamine and metabolites were performed in the dorsal striatum revealing significant increases in DOPAC and HVA. Dopamine receptor agonists and antagonists were used to pharmacologically probe dopamine receptor function. An enhancement of the locomotor suppressing response to dopamine antagonists in Clockdelta19 mice suggested increased dopaminergic tone. Clockdelta19 mice were insensitive to the locomotor stimulating effects of a D1 agonist, but displayed increased levels of D1DR protein. Conversely, the Clockdelta19 mutants displayed enhanced locomotor suppression to a D2 agonist and a coincident increase in D2DR protein. Forskolin stimulation of cAMP resulted in blunted molecular responses in the Clockdelta19 mutants consistent with impairments in D1 signaling and/or enhancements in D2 signaling. In summary, normal CLOCK function appears to be involved in the regulation of dopamine transmission in the striatum. [Keywords: circadian rhythms; dopamine; CLOCK; bipolar disorder; dopamine receptors; tyrosine hydroxylase; ventral tegmental area]