How might circadian rhythms control mood? Let me count the ways.

Abstract

Mood disorders are serious diseases that affect a large portion of the population. There have been many hypotheses put forth over the years to explain the development of major depression, bipolar disorder, and other mood disorders. These hypotheses include disruptions in monoamine transmission, hypothalamus-pituitary-adrenal axis function, immune function, neurogenesis, mitochondrial dysfunction, and neuropeptide signaling (to name a few). Nearly all people suffering from mood disorders have significant disruptions in circadian rhythms and the sleep/wake cycle. In fact, altered sleep patterns are one of the major diagnostic criteria for these disorders. Moreover, environmental disruptions to circadian rhythms, including shift work, travel across time zones, and irregular social schedules, tend to precipitate or exacerbate mood-related episodes. Recent studies have found that molecular clocks are found throughout the brain and body where they participate in the regulation of most physiological processes, including those thought to be involved in mood regulation. This review will summarize recent data that implicate the circadian system as a vital regulator of a variety of systems that are thought to play a role in the development of mood disorders.

Keywords: Bipolar disorder; circadian rhythms; depression; immune system; metabolism; neurogenesis.

Figure 1

This core molecular clock is composed of a series of transcriptional and translational feedback loops. The basic helix-loop-helix-PAS (Period-Arnt-Single-minded)-containing transcription factors, Circadian Locomotor Output Cycles Kaput (CLOCK) and Brain and Muscle Arnt-Like protein 1 (BMAL1; also called MOP3 and ARNTL) heterodimerize and bind to E-box containing sequences in a number of genes including the three Period (Per) genes (Per1, Per2 and Per3) and the two Cryptochrome (Cry) genes (Cry1 and Cry2). Over time, the PER and CRY proteins dimerize and are shuttled back into the nucleus where CRY proteins can directly inhibit the activity of CLOCK and BMAL1 forming a negative feedback loop which cycles every twenty-four hours. In addition to this feedback loop, the CLOCK and BMAL1 proteins regulate the expression of the nuclear hormone receptors, Rev-erbα and Rora which in turn can repress or activate Bmal1 transcription, respectively, through actions at the Rev-Erb/ROR response element in the promoter. Outside of the SCN, Neuronal PAS-Domain Protein 2 (NPAS2; also known as MOP4) can heterodimerize with BMAL1 and control Per and Cry gene expression. There are several key proteins which regulate the timing of the molecular clock through phosphorylation, sumoylation, and other mechanisms. Casein kinase 1 delta and epsilon proteins (CK1δ and CK1ε) phosphorylate the PER, CRY and BMAL1 proteins altering their stability and nuclear entry. Glycogen synthase kinase 3 beta (GSK3β) also phosphorylates the PER2 protein facilitating nuclear entry, the Rev-erbα protein increasing protein stability, and the CRY2 and CLOCK proteins leading to proteasomal degradation.

Figure 2

The circadian system regulates multiple monoaminergic brain regions that control mood, anxiety and motivated behaviors, through local expression of clock genes as well as indirect connections originating from the master pacemaker in the suprachiasmatic nucleus (SCN). The SCN projects monosynaptically to multiple hypothalamic nuclei (in green), which subsequently communicate with regions (in yellow) that synthesize dopamine (DA), serotonin (5-HT) and norepinephrine (NE). As a result, serotonin, norepinephrine and dopamine all have a circadian rhythm in their levels, release, and synthesis-related enzymes. Abbreviations: medial preoptic area (mPOA), sub-paraventricular nucleus of the hypothalamus (sPVN), dorsomedial hypothalamus (DMH), paraventricular nucleus of the thalamus (PVT), dorsal raphe (DR), ventral tegmental area (VTA), locus coeruleus (LC), optic chiasm (OC), corpus callosum (CC), olfactory bulb (OB).

Figure 3

The circadian system regulates many hormones and peptides in the brain and periphery that impact mood and reward. (left panel) The circadian control of the hypothamo-pituitary-adrenal (HPA) axis originates in the SCN which projects to the paraventricular nucleus (PVN) with arginine vasopressin (AVP) synthesizing neurons, causing the release of corticotropin-releasing hormone (CRH). Subsequently, CRH stimulates the synthesis and release of adrenocorticotropin hormone (ACTH) from the anterior pituitary, which travels through the blood stream and stimulates the release of glucocorticoids (GC) from the adrenal gland. Glucocorticoids negatively feedback to multiple sites via interaction with the intracellular glucocorticoid receptor (GR) in order to maintain basal stress hormone levels within a homeostatic range. Rhythmic clock gene expression coordinates incoming hormonal signals to rhythms in local receptor expression at the level of the PVN, pituitary and adrenal gland. (right panel) The hormone leptin is expressed in adipose tissue and is a satiety signal conveying a positive energy balance to the brain. Leptin levels also fluctuate on a daily basis, as clock genes are expressed in adipose tissue, and lead to circadian rhythms in hunger and satiety. Leptin is sleep-inducing and may alter mood by inhibiting orexin neurons in the lateral hypothalamus (LH). An opposing metabolic signal, ghrelin, is released by the stomach to convey a negative energy balance to the brain by stimulating orexigenic Agouti-Related peptide (AgRP)/Neuropeptide Y (NPY)- secreting neurons in the arcuate nucleus of the hypothalamus. Additionally, ghrelin directly stimulates orexinergic neurons in the LH, which induces arousal and feeding behavior. These orexigenic neurons also project directly to dopaminergic neurons in the ventral tegmental area (VTA). Finally, cholecystokinin (CCK) is a circadian regulated peptide that is synthesized in the gut and contributes to feeding behavior, as well as the VTA, which contributes to motivated behavior and reward sensitivity.

Figure 4

The circadian clock influences multiple systems and pathways which are thought to underlie mood disorders. In most cases there are reciprocal interactions which in turn regulate circadian rhythms. Circadian gene mutations might make an individual more vulnerable to mood changes and these are exacerbated by environmental deviations in the daily schedule.