Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice
| Autor: | Rita Barandas, Dominic Landgraf, Christophe D. Proulx, Roberto Malinow, David K. Welsh, Jaimie E. Long |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Circadian clock Mice Transgenic Learned helplessness Anxiety Chronobiology Disorders Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Helplessness Learned Corticosterone Internal medicine medicine Animals Circadian rhythm Biological Psychiatry Behavior Animal Depression Suprachiasmatic nucleus ARNTL Transcription Factors Tail suspension test Circadian Rhythm Mice Inbred C57BL CLOCK Disease Models Animal 030104 developmental biology Endocrinology nervous system Light effects on circadian rhythm chemistry Suprachiasmatic Nucleus sense organs Psychology Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Biological Psychiatry. 80:827-835 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2016.03.1050 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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