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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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.
