The role of the circadian clock in animal models of mood disorders.

Landgraf, Dominic; McCarthy, Michael J.; Welsh, David K.

doi:10.1037/a0036029

Cited by 67 publications

(51 citation statements)

References 188 publications

(245 reference statements)

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“…Although these data do not discriminate between weaker clock gene rhythms in individual MDD subjects and greater variability in phase across subjects [9], they do establish that the molecular machinery of brain circadian clocks is affected in MDD. Another approach to human studies is the investigation of rhythms in cells from patients.…”

Section: Major Depressive Disorder (Mdd) and Bipolar Disorder (Bd)mentioning

confidence: 97%

“…Supporting the notion of clock-stress interaction, Dbp -/-mice appear more vulnerable to stress, gaining more weight and consuming more alcohol than similarly stressed control mice [103]. Mutations of many clock modulating factors, like casein kinase 1δ/ε (CSNK1D/E), f-box/lrr-repeat protein 3 (FBXL3), sodium potassium ATPase (ATP1A3), and glycogen synthase kinase 3B (GSK3B) also lead to mood abnormalities [9]. However, these modulators have additional cellular functions, making the connection between the observed mood-related phenotypes and the circadian clock unclear.…”

Section: Major Depressive Disorder (Mdd) and Bipolar Disorder (Bd)mentioning

confidence: 98%

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Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Landgraf

McCarthy

Welsh

2014

Curr Psychiatry Rep

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144

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Many psychiatric disorders are characterized by circadian rhythm abnormalities including disturbed sleep/wake cycles, changes in locomotor activity, and abnormal endocrine function. Animal models with mutations in circadian "clock genes" commonly show disturbances in reward processing, locomotor activity and novelty seeking behaviors, further supporting the idea of a connection between the circadian clock and psychiatric disorders. However, if circadian clock dysfunction is a common risk factor for multiple psychiatric disorders, it is unknown if and how these putative clock abnormalities could be expressed differently, and contribute to multiple, distinct phenotypes. One possible explanation is that the circadian clock modulates the biological responses to stressful environmental factors that vary with an individual's experience. It is known that the circadian clock and the stress response systems are closely related: Circadian clock genes regulate the physiological sensitivity to, and rhythmic release of glucocorticoids (GC). In turn, GCs have reciprocal effects on the clock. Since stressful life events or increased vulnerability to stress are risk factors for multiple psychiatric disorders including posttraumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BD), major depressive disorder (MDD), alcohol use disorder (AUD) and schizophrenia (SCZ), we propose that modulation of the stress response is a common mechanism by which circadian clock genes affect these illnesses. Presently, we review how molecular components of the circadian clock may contribute to these six psychiatric disorders, and present the hypothesis that modulation of the stress response may constitute a common mechanism by which the circadian clock affects multiple psychiatric disorders.

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Section: Major Depressive Disorder (Mdd) and Bipolar Disorder (Bd)mentioning

confidence: 97%

Section: Major Depressive Disorder (Mdd) and Bipolar Disorder (Bd)mentioning

confidence: 98%

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Landgraf

McCarthy

Welsh

2014

Curr Psychiatry Rep

Self Cite

144

100

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“…For example, disruption of circadian rhythms is a hallmark of most neuropsychiatric disorders, including bipolar disorder (BD) (Landgraf et al, 2014a;McCarthy and Welsh, 2012;Wulff et al, 2010), a disabling condition characterized by episodes of depression and mania. The mechanisms by which circadian and mood-regulating processes influence each other are unclear (Landgraf et al, 2014b). In the case of BD, however, manic behavior is associated with elevated levels of dopamine (DA) (van Enkhuizen et al, 2015), a neurotransmitter that also impacts circadian rhythms.…”

Section: Introductionmentioning

confidence: 99%

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

et al. 2016

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a b s t r a c tEndogenous circadian (~24 h) clocks regulate key physiological and cognitive processes via rhythmic expression of clock genes. The main circadian pacemaker is the hypothalamic suprachiasmatic nucleus (SCN). Mood disorders, including bipolar disorder (BD), are commonly associated with disturbed circadian rhythms. Dopamine (DA) contributes to mania in BD and has direct impact on clock gene expression. Therefore, we hypothesized that high levels of DA during episodes of mania contribute to disturbed circadian rhythms in BD. The mood stabilizer valproic acid (VPA) also affects circadian rhythms. Thus, we further hypothesized that VPA normalizes circadian disturbances caused by elevated levels of DA. To test these hypotheses, we examined locomotor rhythms and circadian gene cycling in mice with reduced expression of the dopamine transporter (DAT-KD mice), which results in elevated DA levels and manialike behavior. We found that elevated DA signaling lengthened the circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants. In contrast, we found that VPA shortened circadian period of behavioral rhythms in DAT-KD mice and clock gene expression rhythms in SCN explants, hippocampal cell lines, and human fibroblasts from BD patients. Thus, DA and VPA have opposing effects on circadian period. To test whether the impact of VPA on circadian rhythms contributes to its behavioral effects, we fed VPA to DAT-deficient Drosophila with and without functioning circadian clocks. Consistent with our hypothesis, we found that VPA had potent activity-suppressing effects in hyperactive DAT-deficient flies with intact circadian clocks. However, these effects were attenuated in DAT-deficient flies in which circadian clocks were disrupted, suggesting that VPA functions partly through the circadian clock to suppress activity. Here, we provide in vivo and in vitro evidence across species that elevated DA signaling lengthens the circadian period, an effect remediated by VPA treatment. Hence, VPA may exert beneficial effects on mood by normalizing lengthened circadian rhythm period in subjects with elevated DA resulting from reduced DAT.

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“…Brdm1-/-mutant mice display a depression-like phenotype, and Cry1 -/-; Cry2 -/-mutant mice display higher anxiety levels, sensitivity to psychostimulant drugs, and perturbed cognitive functions such as recognition memory [49].…”

Section: Per1mentioning

confidence: 99%

“…Animal models carrying mutations in clock genes often show behaviors comparable to human symptoms of depression or mania [49]. The best studied clock gene model of a mood disorder is the Clock-Δ19 mouse [50], which carries a dominant-negative mutation in the essential circadian clock gene Clock, and displays manic-like behavioral features of hyperactivity, impulsivity, increased preference for psychostimulants and decreased sleep.…”

Section: Animal Models Of Clock Dysfunctionmentioning

confidence: 99%

Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders

Barandas

Landgraf

McCarthy

et al. 2015

Curr Psychiatry Rep

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Psychiatric disorders such as schizophrenia, bipolar disorder, and major depressive disorder are often accompanied by metabolic dysfunction symptoms, including obesity and diabetes. Since the circadian system controls important brain systems that regulate affective, cognitive, and metabolic functions, and neuropsychiatric and metabolic diseases are often correlated with disturbances of circadian rhythms, we hypothesize that dysregulation of circadian clocks plays a central role in metabolic comorbidity in psychiatric disorders. In this review paper, we highlight the role of circadian clocks in glucocorticoid, dopamine, and orexin/melanin-concentrating hormone systems, and describe how a dysfunction of these clocks may contribute to the simultaneous development of psychiatric and metabolic symptoms.3

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The role of the circadian clock in animal models of mood disorders.

Cited by 67 publications

References 188 publications

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders

The mood stabilizer valproic acid opposes the effects of dopamine on circadian rhythms

Circadian Clocks as Modulators of Metabolic Comorbidity in Psychiatric Disorders

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