Circadian rhythms and mood regulation: insights from pre-clinical models

Abstract

Affective disorders such as major depression, bipolar disorder, and seasonal affective disorder are associated with major disruptions in circadian rhythms. Indeed, altered sleep/wake cycles are a critical feature for diagnosis in the DSM IV and several of the therapies used to treat these disorders have profound effects on rhythm length and stabilization in human populations. Furthermore, multiple human genetic studies have identified polymorphisms in specific circadian genes associated with these disorders. Thus, there appears to be a strong association between the circadian system and mood regulation, although the mechanisms that underlie this association are unclear. Recently, a number of studies in animal models have begun to shed light on the complex interactions between circadian genes and mood-related neurotransmitter systems, the effects of light manipulation on brain circuitry, the impact of chronic stress on rhythms, and the ways in which antidepressant and mood-stabilizing drugs alter the clock. This review will focus on the recent advances that have been gleaned from the use of pre-clinical models to further our understanding of how the circadian system regulates mood.

Figure 1. The circadian system is controlled by many factors

The SCN is the master pacemaker in the brain. It is responsive to light and orchestrates the timing of rhythms in other regions of the brain and throughout the body. In turn, various hormones and peptides produced in the periphery can influence rhythms in the brain. Other environmental influences like food and stress also impact rhythms in the brain and body. The cellular clock is a transcriptional translational feedback loop. CLOCK/BMAL1 dimers regulate the expression of Per and Cry genes. The PER and CRY proteins are modified by various kinases including CK1 and GSK3β and they ultimately feed back into the nucleus and inhibit their own transcription. NPAS2 functions similarly to CLOCK in certain brain regions. RevErbα inhibits while Rorα enhances Bmal1 transcription as part of a secondary loop.