Circadian rhythms and mood disorders: Time to see the light

Abstract

The importance of time is ever prevalent in our world, and disruptions to the normal light/dark and sleep/wake cycle have now become the norm rather than the exception for a large part of it. All mood disorders, including seasonal affective disorder (SAD), major depressive disorder (MDD), and bipolar disorder (BD), are strongly associated with abnormal sleep and circadian rhythms in a variety of physiological processes. Environmental disruptions to normal sleep/wake patterns, light/dark changes, and seasonal changes can precipitate episodes. Moreover, treatments that target the circadian system have proven to be therapeutic in certain cases. This review will summarize much of our current knowledge of how these disorders associate with specific circadian phenotypes, as well as the neuronal mechanisms that link the circadian clock with mood regulation. We also discuss what has been learned from therapies that target circadian rhythms and how we may use current knowledge to develop more individually designed treatments.

Keywords: bipolar disorder; chronotherapy; depression; seasonal affective disorder; sleep.

Figure 1.. The Retinohypothalamic circuit responds to light from the environment and uses it to entrain internal rhythms.

Light information is directly projected to the SCN through the retinal hypothalamic tract. Starting in the retina, it travels to ventral core of the SCN in the hypothalamus which communicates with the dorsal shell that houses the endogenous pacemaker. The bidirectional communication between the shell and core together entrain and synchronize peripheral clocks in the brain and body.

Figure 2.. Circadian rhythm perturbations as depicted through activity patterns.

Daylight hours (yellow), darkness (blue), activity periods (black bars (1 line = 1 day) 1) Entrained rhythms align with the light/dark cycle, 2) delays are shifted with onset occurring later than observed entrained rhythms, 3) advances are shifted to occur earlier than usual, 4) fragmentation is a breakdown and disorganization of entrained rhythms, and 5)free running conditions are the absence of cues or the inability of rhythms to entrain to external cues.

Figure 3.. Molecular machinery of the circadian clock.

Circadian locomotor output cycles kaput (CLOCK) and brain and muscle Arnt-like protein 1 (BMAL1; a.k.a. ARNTL) heterodimerize and bind to Enhancer Box (E-box) elements to activate clock-controlled genes (CCGs) transcription, including the Period (Per) and Cryptochrome (Cry) genes. PER and CRY proteins dimerize and translocate back to the nucleus to inhibit CLOCK and BMAL1 activity, forming a negative loop, which cycles every 24 hours. In a secondary loop, CLOCK and BMAL1 proteins regulate the nuclear hormone receptors expression, Rev-erb and Ror, which inhibit or activate Bmal1 transcription, respectively.

Figure 4.. Melatonin secretion duration changes as a function of seasonal night length.

The summer melatonin secretion profile (Left) is shorter due to summers longer daylight hours suppressing melatonin secretion. In the winter (Right) melatonin secretion is longer because of the shorter daylight hours. The variation in melatonin secretion duration and amplitude changes are a factor of seasonal daylight presence allowing it to act as both a seasonal and night timekeeper.

Figure 5.. Mood Regulation by circadian rhythms and the environment.

There is a complex interplay between circadian rhythms, the environment, sleep and mood regulation. The circadian clock affects multiple brain regions and systems and certain mutations in the circadian genes might make an individual more vulnerable to mood disorders. Environmental factors such as seasonal changes, stress or night shift work can lead to sleep and circadian dysfunction and contribute to mood changes. DA, dopamine; 5-HT, serotonin; NE, norepinephrine; MEL, melatonin; SCN, suprachiasmatic nucleus; HPA, hypothalamus-pituitary-adrenal.