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

TitleGenetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.
Publication TypeJournal Article
Year of Publication2016
AuthorsLandgraf, D, Long, JE, Proulx, CD, Barandas, R, Malinow, R, Welsh, DK
JournalBiol Psychiatry
Date Published2016 12 01
KeywordsAnimals, Anxiety, ARNTL Transcription Factors, Behavior, Animal, Chronobiology Disorders, Circadian Rhythm, Depression, Disease Models, Animal, Helplessness, Learned, Mice, Mice, Inbred C57BL, Mice, Transgenic, Suprachiasmatic Nucleus

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.

Alternate JournalBiol. Psychiatry
PubMed ID27113500
PubMed Central IDPMC5102810
Grant ListI01 BX001146 / BX / BLRD VA / United States
R01 MH049159 / MH / NIMH NIH HHS / United States
R01 MH091119 / MH / NIMH NIH HHS / United States