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Biol Psychiatry. 2016 Dec 1;80(11):827-835. doi: 10.1016/j.biopsych.2016.03.1050. Epub 2016 Mar 10.

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.

Author information

1
Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, California. Electronic address: dolandgraf@gmail.com.
2
Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, California.
3
Department of Neurosciences, University of California, San Diego, La Jolla, California.
4
Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, California; Department of Psychiatry, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, University of Lisbon, Lisbon, Portugal; Faculty of Medicine, University of Lisbon, Lisbon, Portugal.

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:

Circadian clocks; Corticosterone; Depression; Learned helplessness; Mouse model; Suprachiasmatic nucleus

Comment in

PMID:
27113500
PMCID:
PMC5102810
DOI:
10.1016/j.biopsych.2016.03.1050
[Indexed for MEDLINE]
Free PMC Article

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