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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Anxiety / etiology*
  • Behavior, Animal / physiology*
  • Chronobiology Disorders / complications*
  • Chronobiology Disorders / genetics
  • Circadian Rhythm / genetics
  • Circadian Rhythm / physiology*
  • Depression / etiology*
  • Disease Models, Animal*
  • Helplessness, Learned
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Suprachiasmatic Nucleus / physiopathology*

Substances

  • ARNTL Transcription Factors
  • Arntl protein, mouse