Abstract
Background
Major depressive disorder is associated with disturbed circadian rhythms. To investigate
the causal relationship between mood disorders and circadian clock disruption, previous
studies in animal models have employed light/dark manipulations, global mutations
of clock genes, or brain area lesions. However, light can impact mood by noncircadian
mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions
not only disrupt cellular circadian rhythms but also destroy cells and eliminate important
neuronal connections, including light reception pathways. Thus, a definitive causal
role for functioning circadian clocks in mood regulation has not been established.
Methods
We stereotactically injected viral vectors encoding short hairpin RNA to knock down
expression of the essential clock gene Bmal1 into the brain’s master circadian pacemaker, the suprachiasmatic nucleus (SCN).
Results
In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were
maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal
connections were undisturbed, including photic inputs. In the learned helplessness
paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also
spent more time immobile in the tail suspension test and less time in the lighted
section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone,
and an attenuated increase of corticosterone in response to stress.
Conclusions
Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair,
and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression.
Keywords
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References
- Suprachiasmatic nucleus: Cell autonomy and network properties.Annu Rev Physiol. 2010; 72: 551-577
- Central projections of melanopsin-expressing retinal ganglion cells in the mouse.J Comp Neurol. 2006; 497: 326-349
- The light-dark cycle controls peripheral rhythmicity in mice with a genetically ablated suprachiasmatic nucleus clock.FASEB J. 2014; 28: 4950-4960
- Light stimulates the mouse adrenal through a retinohypothalamic pathway independent of an effect on the clock in the suprachiasmatic nucleus.PloS One. 2014; 9: e92959
- The circadian rhythm of glucocorticoids is regulated by a gating mechanism residing in the adrenal cortical clock.Cell Metab. 2006; 4: 163-173
- Light activates the adrenal gland: timing of gene expression and glucocorticoid release.Cell Metab. 2005; 2: 297-307
- Circadian rhythms and depression.Aust Fam Physician. 2010; 39: 307-310
- Rhythm and mood: Relationships between the circadian clock and mood-related behavior.Behav Neurosci. 2014; 128: 326-343
- Cellular circadian clocks in mood disorders.J Biol Rhythms. 2012; 27: 339-352
- Circadian genes, rhythms and the biology of mood disorders.Pharmacol Ther. 2007; 114: 222-232
- Circadian rhythms and depression: Human psychopathology and animal models.Neuropharmacology. 2012; 62: 101-114
- Circadian patterns of gene expression in the human brain and disruption in major depressive disorder.Proc Natl Acad Sci U S A. 2013; 110: 9950-9955
- The role of the circadian clock in animal models of mood disorders.Behav Neurosci. 2014; 128: 344-359
- Chronobiological disturbances with hyperthermia and hypercortisolism induced by chronic mild stress in rats.Behav Brain Res. 2006; 173: 326-330
- Effect of chronic mild stress on circadian rhythms in the locomotor activity in rats.Pharmacol Biochem Behav. 1996; 54: 229-234
- Chronic stress induces brain region-specific alterations of molecular rhythms that correlate with depression-like behavior in mice.Biol Psychiatry. 2015; 78: 249-258
- Diurnal oscillation of amygdala clock gene expression and loss of synchrony in a mouse model of depression.Int J Neuropsychopharmacol. Dec 11. 2014; 18
- Is shift work making your patient sick? Emerging theories and therapies for treating shift work disorder.Postgrad Med. 2011; 123: 106-115
- Constant darkness induces IL-6-dependent depression-like behavior through the NF-kappaB signaling pathway.J Neurosci. 2011; 31: 9075-9083
- Neurotransmitter switching in the adult brain regulates behavior.Science. 2013; 340: 449-453
- Light deprivation damages monoamine neurons and produces a depressive behavioral phenotype in rats.Proc Natl Acad Sci U S A. 2008; 105: 4898-4903
- Effect of lesioning the suprachiasmatic nuclei on behavioral despair in rats.Brain Res. 2004; 1001: 118-124
- In search of a depressed mouse: Utility of models for studying depression-related behavior in genetically modified mice.Mol Psychiatry. 2004; 9: 326-357
- Circadian rhythm. Dysrhythmia in the suprachiasmatic nucleus inhibits memory processing.Science. 2014; 346: 854-857
- PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues.Proc Natl Acad Sci U S A. 2004; 101: 5339-5346
- Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression.Curr Biol. 2004; 14: 2289-2295
- Dissociation of learned helplessness and fear conditioning in mice: a mouse model of depression.PloS One. 2015; 10: e0125892
- Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal gray.Eur J Neurosci. 2015; 43: 1309-1320
- Circadian clock and stress interactions in the molecular biology of psychiatric disorders.Curr Psychiatry Rep. 2014; 16: 483
- Circadian rhythms in depression and recovery: Evidence for blunted amplitude as the main chronobiological abnormality.Psychiatry Res. 1989; 28: 263-278
- A pilot study of the phase angle between cortisol and melatonin in major depression—a potential biomarker?.J Psychiatr Res. 2010; 44: 69-74
- Circadian misalignment in major depressive disorder.Psychiatry Res. 2009; 168: 259-261
- Evening preference is related to the incidence of depressive states independent of sleep-wake conditions.Chronobiol Int. 2010; 27: 1797-1812
- Rodent models in depression research: Classical strategies and new directions.Ann Med. 2010; 42: 252-264
- Stress models of depression: Forming genetically vulnerable strains.Neurosci Biobehav Rev. 2005; 29: 799-804
- Effects of bilateral adrenalectomy on the induction of learned helplessness behavior.Neuropsychopharmacology. 1990; 3: 109-114
- Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.Rheumatology (Oxford). 2000; 39: 764-771
- Blood corticosterone and resistance to hypoxia during operant learning and development of learned helplessness [in Russian].Biull Eksp Biol Med. 1999; 128: 29-31
- Intercellular coupling confers robustness against mutations in the SCN circadian clock network.Cell. 2007; 129: 605-616
- Circadian clocks as modulators of metabolic comorbidity in psychiatric disorders.Curr Psychiatry Rep. 2015; 17: 98
Article Info
Publication History
Published online: March 10, 2016
Accepted:
March 4,
2016
Received in revised form:
March 4,
2016
Received:
August 11,
2015
Identification
Copyright
© 2016 Published by Elsevier Inc. All rights reserved.
ScienceDirect
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- Sleep and Mood: Chicken or Egg?Biological PsychiatryVol. 80Issue 11
- PreviewIt has long been recognized that there is an association between sleep and mood. Both of these phenomena are light-sensitive; light entrains the circadian clock, and too little light predisposes a significant portion of the population to seasonal affective disorder. Sleep deprivation can precipitate mania in patients with bipolar disease (1) but can also be an effective treatment for “breaking” a bout of pharmacologically refractory depression (2). Glycogen synthase kinase 3 beta has been shown to be a circadian gene in flies (3) and mammals (4) and is a target of lithium therapy, which is useful in many patients with bipolar disease.
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