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



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).



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.



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.
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.
Dominic
D
Landgraf
Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, California.
Jaimie E
JE
Long
Department of Neurosciences, University of California, San Diego, La Jolla, California.
Christophe D
CD
Proulx
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.
Rita
R
Barandas
Department of Neurosciences, University of California, San Diego, La Jolla, California.
Roberto
R
Malinow
Veterans Affairs San Diego Healthcare System, San Diego; Department of Psychiatry and Center for Circadian Biology, University of California, San Diego, La Jolla, California.
David K
DK
Welsh
D056930:ARNTL Transcription Factors; D000818:Animals; D001007:Anxiety / Q000209:etiology*; D001522:Behavior, Animal / Q000502:physiology*; D021081:Chronobiology Disorders / Q000150:complications* / Q000235:genetics; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology*; D003863:Depression / Q000209:etiology*; D004195:Disease Models, Animal; D006380:Helplessness, Learned; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013493:Suprachiasmatic Nucleus / Q000503:physiopathology*
D056930:ARNTL Transcription Factors; C538961:Bmal1 protein, mouse
Circadian clocks; Corticosterone; Depression; Learned helplessness; Mouse model; Suprachiasmatic nucleus