Nearly all individuals suffering from mood disorders have abnormalities in their sleep/wake and other daily rhythms. Furthermore, many of the successful treatments for these disorders have dramatic effects on circadian rhythms and this action correlates with patient improvement. However, it is uncertain whether the abnormal clock function that is widely reported in these individuals underlies the development of mood disorders, or if the disruptions in rhythms are a byproduct from other disrupted circuits. Moreover, the mechanism by which the circadian clock might regulate mood is currently unknown. Our data suggests that the genes that make up the circadian clock play a key role in the regulation of depression-like and manic-like behavior in mouse models. Furthermore, at least a portion of the behavioral responses associated with depression or mania appears to be regulated by circadian gene expression outside of the central pacemaker of the suprachiasmatic nucleus (SCN). We hypothesize that the central clock of the SCN affects peripheral clocks in reward and mood-related regions of the brain such as the ventral tegmental area (VTA). Indeed the core circadian clock genes are expressed there, and several genes known to play an important role in mood regulation have robust circadian rhythms in expression in this regions. If this connection between the SCN and these regions becomes out of sync or disrupted, this could potentially lead to depressive or manic episodes. This proposal utilizes both a mouse model of depression and a mouse model of mania that we have recently described to explore the underling biology between the circadian clock and mood regulation. Furthermore, we will determine how the treatments for mania and depression affect behavioral and molecular rhythms, and if these changes are important for therapeutic efficacy.

Public Health Relevance

Depression and other mood disorders are among the most common forms of psychiatric illness. A strong association between disruptions in circadian rhythms and these disorders has been reported for many years. However, it is unclear whether underlying clock abnormalities are the cause of these disorders, or how disruptions in the circadian system could lead to changes in mood. Through these proposed experiments, we seek to understand this connection between circadian rhythms and mood disorders, and explore the potential mechanisms that underlie this association. These experiments could lead us to more targeted treatments for these devastating disorders in the future.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Winsky, Lois M
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University of Pittsburgh
Schools of Medicine
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Ozburn, Angela R; Falcon, Edgardo; Twaddle, Alan et al. (2015) Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol Psychiatry 77:425-33
Arey, R N; Enwright 3rd, J F; Spencer, S M et al. (2013) An important role for Cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mol Psychiatry :
Kumar, Jaswinder; Chuang, Jen-Chieh; Na, Elisa S et al. (2013) Differential effects of chronic social stress and fluoxetine on meal patterns in mice. Appetite 64:81-8
McClung, Colleen A (2013) How might circadian rhythms control mood? Let me count the ways... Biol Psychiatry 74:242-9
Spencer, Sade; Falcon, Edgardo; Kumar, Jaswinder et al. (2013) Circadian genes Period 1 and Period 2 in the nucleus accumbens regulate anxiety-related behavior. Eur J Neurosci 37:242-50
Coque, Laurent; Mukherjee, Shibani; Cao, Jun-Li et al. (2011) Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the Clockýý19 mouse model of mania. Neuropsychopharmacology 36:1478-88
McClung, Colleen A (2011) Circadian rhythms and mood regulation: insights from pre-clinical models. Eur Neuropsychopharmacol 21 Suppl 4:S683-93
Dzirasa, Kafui; McGarity, DeAnna L; Bhattacharya, Anirban et al. (2011) Impaired limbic gamma oscillatory synchrony during anxiety-related behavior in a genetic mouse model of bipolar mania. J Neurosci 31:6449-56
Mukherjee, Shibani; Coque, Laurent; Cao, Jun-Li et al. (2010) Knockdown of Clock in the ventral tegmental area through RNA interference results in a mixed state of mania and depression-like behavior. Biol Psychiatry 68:503-11