ReviewCircadian rhythms and depression: Human psychopathology and animal models
Highlights
► Circadian rhythms are central to life, health and disease. ► Significant data supports connections between circadian rhythms and depression. ► The underlying mechanisms connecting rhythms and depression are not clear. ► One of the limitations of related research is the lack of good animal models. ► New ideas may lead to better models and advances in mechanistic understanding.
Introduction
In this review we explore the relationship between circadian rhythms and depression. First, we present the evolution and adaptive value of circadian rhythms, and point to possible health consequences of disruptions in this system. Then, we review a number of lines of evidence supported by human as well as animal models data indicating the involvement of circadian rhythms in depression. Some of the main interactions between depression and circadian rhythms are presented schematically in Fig. 1.
We live in a rhythmic world. The rotation of earth around itself and around the sun causes daily and seasonal rhythms in light intensity, ambient temperature, humidity, and more. To optimally adapt to these rhythms, most organisms (including humans) developed rhythms in almost every aspect of their body, ranging from gene expression (expression levels of approximately 15% of the genes in our body show daily rhythms), physiology (e.g., heart rate, metabolism, and hormone secretion), cognitive functions (e.g., learning, memory) and activity-rest patterns.
Being active at different times, on the diel or the seasonal scale, exposes animals to very different environmental conditions. Confining activity to part of the temporal spectrum allows animal species to adapt to these conditions on an evolutionary scale (Kronfeld-Schor and Dayan, 2003, Kronfeld-Schor and Dayan, 2008, Kronfeld-Schor et al., 2000). As a consequence of these different adaptations, the environment of an organism is divided into times when it is optimal to perform a certain activity, and times when performing the same activity may even be disadvantageous. Hence, it is not surprising that most animals have a distinct activity pattern confined to a certain part of the diel cycle, which is typical to the species, and to which they are adapted behaviorally, anatomically, and physiologically (Daan, 1981, DeCoursey, 2004). The earliest mammals were nocturnal insectivores (Crompton, 1980) and although most current mammals are still nocturnal, independent evolutionary transitions to a diurnal pattern of adaptation to the day/night cycle have occurred over the course of evolution. Humans are one of the species which developed to be active during the daytime.
As part of the adaptations to the rhythmic world, virtually all species studied so far developed an internal circadian timing system, composed of a master clock, which in mammals is located in the in the Suprachiasmatic Nucleus [the SCN (Klein et al., 1991, Moore-Ede et al., 1982)], and subsidiary clocks in nearly every body cell (Dibner et al., 2010). This internal timing system allows the individual to prepare itself, rather than respond, to the changing environment, to choose the right time for a given response or activity without being easily mislead by minor environmental changes, and to assure that a temporal order between internal processes and between them and the environment maximizes performance. A disruption of the circadian clock, or activity during the abnormal part of the diel cycle (as in the case of shift-work, late evening activity or jet leg) may result in misalignment between the internal circadian clock and the activity pattern, which may have adverse consequences such as metabolic syndrome, obesity, insomnia, increased risk of cancer, as well as other physiological and mental disorders (Albrecht, 2010, Arble et al., 2009, Karatsoreos et al., 2011, Scheer et al., 2009).
Section snippets
The relationship between circadian rhythms and depression
Many lines of evidence in humans as well as in animal models clearly demonstrate relationship between depression and circadian rhythms. These lines of evidence stem from (A) disease patterns, mechanisms and models; (B) treatment effects in patients and in animal models. Regarding disease patterns, some important and established connections include: (1) daily patterns of depression; (2) changes in physiological and behavioral daily rhythms in depressed patients and in animal models of
Conclusion
The connections between circadian rhythms and depression are now well established and supported by several unrelated lines of evidence in humans with at least some support from work with animal models. Nevertheless, the mechanisms underlying the specific biology of the interactions between circadian rhythms and affect are yet to be studied. In the current review we suggest that the identification of better animal models with better homology to the circadian rhythms of humans may be a
Role of funding sources
Some of the studies described in this manuscript were funded by (1) the National Institute for Psychobiology in Israel, founded by the Charles E. Smith Family and (2) University of Minnesota Graduate School Grant in Aid. Funding agencies had no influence on study design, collection, analysis, and interpretation of data, writing of the report or the decision to submit the paper for publication.
Acknowledgments
We would like to acknowledge the help of Tal Ashkenazy-Frolinger, Katy Krivisky and Shlomit Flaisher-Grinberg for their participation and contribution to some of the studies described in the paper. We would also like to thank Prof. David Eilam for his assistance and intellectual contribution in the initial phase of the diurnal model project.
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