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
AuteursLandgraf, D, Long, JE, Proulx, CD, Barandas, R, Malinow, R, Welsh, DK
JournalBiol Psychiatry
Volume80
Issue11
Pagination827-835
Date Published2016 12 01
ISSN1873-2402
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
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.

DOI10.1016/j.biopsych.2016.03.1050
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