Rhythms of life: circadian disruption and brain disorders across the lifespan

Abstract

Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.

Fig. 1 |. The circadian timing system.

a | The circadian timing system synchronizes clocks across the entire body to adapt and optimize physiology to changes in our environment. Light is received by specialized melanopsin-producing photoreceptive retinal ganglion cells (ipRGCs) in the eye. These ipRGCs project through the retinohypothalamic tract to the suprachiasmatic nucleus (SCN), among other brain regions. The SCN relays timing information to other areas of the brain via direct projections (dark green boxes) and indirect projections (light green boxes). Humoral signals and the peripheral nervous system (that is, the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS)) convey information from the SCN to orchestrate peripheral clocks. Feeding schedules and exercise can also entrain central and peripheral clocks. Circadian rhythms are key regulators of thermogenesis, immune function, metabolism, reproduction and stem cell development. b | The mammalian molecular clock is composed of transcriptional and translational feedback loops that oscillate with a near-24-hour cycle. The positive loop is driven by the heterodimerization of either circadian locomotor output cycles protein kaput (CLOCK) or neuronal PAS domain-containing protein 2 (NPAS2) with brain and muscle ARNT-like 1 (BMAL1) in the nucleus. The resulting heterodimers bind to enhancer boxes (E-boxes) in gene promoters to regulate the transcription of clock-controlled genes (CCGs), including those encoding period (PER) proteins and cryptochrome (CRY) proteins. PER and CRY proteins accumulate in the cytoplasm during the circadian cycle, eventually dimerizing and shuttling to the nucleus to inhibit their own transcription, thus closing the negative-feedback loop. The auxiliary loop includes the nuclear retinoic acid receptor-related orphan receptors (RORα and RORβ) and REV-ERBs (REV-ERBα and REV-ERBβ), which are also transcriptionally regulated by CLOCK–BMAL1 heterodimers. REV-ERBα (REV in the figure) and RORα repress and activate the transcription of Bmal1, respectively, by inhibiting and activating the ROR or REV-ERB response elements (RREs). CLOCK–BMAL1 complexes also control the expression of nicotinamide phosphori-bosyltransferase (NAMPT), which is the rate-limiting enzyme of NAD⁺ biosynthesis from nicotinamide (NAM). NAM is modified by NAMPT to produce nicotinamide mononucleotide (NMN), which in turn is converted to NAD⁺ by several adenyltransferases. Thus, NAMPT oscillations control circadian fluctuations in NAD⁺ levels, which in turn modulate sirtuin 1 (SIRT1) activity and signalling. High levels of NAD⁺ promote SIRT1 activation. SIRT1 interacts directly with CLOCK–BMAL1 to deacetylate BMAL1 and inhibit CLOCK-driven transcription. Between tissues and cell types, CCGs and other molecular and cellular rhythms may be expressed with different acrophases (phase of peak expression), amplitudes and even periodicities. ArcN, arcuate nucleus; DmH, dorsomedial hypothalamus; DR, dorsal raphe; IGL, intergeniculate leaflet; LC, locus coeruleus; LH, lateral hypothalamus; LHb, lateral habenula; MA, medial amygdala; mPOA, medial preoptic area; NAc, nucleus accumbens; PVN, paraventricular nucleus of the hypothalamus; PVT, paraventricular nucleus of the thalamus; RMTg, rostromedial tegmental nucleus; Sptm, septum; SPZ, subparaventricular zone; VLPO, ventrolateral preoptic nucleus; VTA, ventral tegmental area.

Fig. 2 |. rhythms across the lifespan.

Schematic of circadian rhythm changes from infancy, adolescence, adulthood and older age. During infancy, sleep–wake rhythms are ultradian and consolidate during the first year of development. From childhood to adolescence, there is a marked shift from an early to a late chronotype, which subsequently becomes earlier during adulthood, with shorter sleep durations through adulthood. Rhythms undergo a gradual loss of amplitude with ageing. Temperature rhythms peak during childhood, and amplitudes steadily reduce during ageing. Melatonin rhythms are delayed during adolescence, with overall levels peaking during childhood and considerably decreasing during ageing. Similarly, rodent studies have demonstrated that suprachiasmatic nucleus (SCN) activity rhythms gradually decline with ageing (not shown). Cortisol rhythms peak earlier in the morning during childhood and, with age, gradually widen and reduce in overall amplitude. The amplitude of rhythmic gene expression in the brain and other tissues is reduced during ageing, affecting tissue homeostasis and function (not shown).

Fig. 3 |. Maternal and fetal rhythms.

Fetal tissues such as adrenal glands and the suprachiasmatic nucleus (SCN) may be entrained by rhythms of maternal feeding schedules, core body temperature and melatonin. Entraining signals, including melatonin and glucocorticoids, may cross the placental barrier to entrain, modulate or aid the development of fetal circadian rhythms among brain and peripheral tissues. ANS, autonomic nervous system; RHT, retinohypothalamic tract.

Fig. 4 |. Effects of social constraints, sleep and circadian disruptions on adolescent brain function.

A proposed model for the associations between sleep, circadian rhythms and psychiatric disorders during adolescence. Neural circuits responsible for controlling cognition, mood and reward mature rapidly during adolescence and may be negatively affected by sleep deprivation and circadian misalignment, potentially leading to poor decision making, impulsivity and risky behaviours. Basic and clinical studies have linked circadian genes and their variants to corticostriatal dopamine and glutamatergic signalling that are important for cognition, mood and reward. These changes contribute to the vulnerability of developing psychiatric disorders. Several psychiatric disorders, including mood disorders, substance use disorders and schizophrenia, are associated with alterations in rhythms and/or sleep that affect cognition, motivation and impulsivity. Sleep and/or circadian rhythm disruptions (for example, genetic and/or environmental perturbations) are also associated with vulnerability to and the progression of psychiatric disorders. Interventions for targeting sleep and/or circadian rhythms may be therapeutically effective for treating disorders that emerge during vulnerable periods of adolescence.

Fig. 5 |. circadian regulation of dopamine.

The ventral tegmental area (VTA)–nucleus accumbens (NAc) circuitry is regulated by a local molecular clock, which controls the transcription of genes involved in the dopamine (DA) signalling pathway, including those encoding: tyrosine hydroxylase (TH), the major rate-limiting enzyme converting tyrosine to the DA precursor l-dihydroxyphenylalanine (l-DOPA); cholecystokinin (CCK), a neuropeptide released from presynaptic DA terminals to suppress further DA release; and monoamine oxidase A (MAOA), a mitochondrial enzyme used to metabolize monoamine neurotransmitters, including DA. For example, the circadian transcription factors of circadian locomotor output cycles protein kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1) form heterodimers and recruit the metabolic sensor and histone acetylase sirtuin 1 (SIRT1) to the enhancer box (E-box) within the TH promoter to repress transcription by cAMP response element-binding protein (CREB). CREB activates TH transcription via the CRE site, located proximal to the transcription start site and the circadian E-box. In addition, CLOCK is capable of binding the E-box within the Cck promoter to promote the transcription of Cck in the VTA. Mixed lineage leukaemia protein 1 (MLL1) is also recruited to CLOCK–BMAL1 heterodimers to promote the transcription of target genes via histone acetylation. REV-ERBα (REV) also represses transcription by binding the REV-ERB response element (RRE) promoter site in antiphase with the transcription factor NURR1 at the NURR1 binding motif, NBRE. Presynaptic dopamine 2 receptors (D2Rs) may also be regulated by the molecular clock. Diurnal rhythms of dopamine, glutamate and GABA levels, as well as of the expression and activity of their receptors, are present in the NAc, potentially temporally gating and promoting neuronal responses during certain times of day. DAT, DA transporter; DOPAC, 3–4-dihydroxyphenylacetic acid; GABAR, GABA receptor; Glu, glutamate; GluR, glutamate receptor (ionotropic).