Article

Circadian rhythms: Depression brought to light.

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
Nature (Impact Factor: 42.35). 11/2012; DOI: 10.1038/nature11752
Source: PubMed

ABSTRACT Exposure to abnormal light-dark cycles causes depression-like behaviour
and learning deficits in mice. The defects seem to occur independently
of disturbances to sleep and other processes regulated by the biological
clock. See Letter p.594

0 Bookmarks
 · 
183 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
    Science 02/2006; 311(5762):864-8. DOI:10.1126/science.1120972 · 31.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.
    Nature 06/2011; 475(7354):91-5. DOI:10.1038/nature10130 · 42.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.
    Annual Review of Neuroscience 04/2012; 35:445-62. DOI:10.1146/annurev-neuro-060909-153128 · 22.66 Impact Factor

Full-text

Download
62 Downloads
Available from
May 20, 2014