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's 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.
Circadian rhythms are near-24-hour oscillations found in essentially every physiological process in the human brain and body. The suprachiasmatic nucleus (SCN) in the hypothalamus serves as the master pacemaker that sets the timing of rhythms by regulating neuronal activity, body temperature, and hormonal signals. (FIG. 1).
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 phosphoribosyltransferase (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.
In individual cells, molecular rhythms are generated by a transcriptional–translational feedback loop involving core transcriptional activators — circadian locomotor output cycles kaput (CLOCK), the closely related neuronal PAS domain protein 2 (NPAS2) and brain and muscle ARNT-like protein 1 (BMAL1) — that regulate the expression of many genes, including those encoding period (PER) and cryptochrome (CRY). which, once translated, inhibit their own transcription. Many other proteins, including various kinases, phosphatases and other transcriptional cofactors, regulate this core molecular clock (FIG. 1).
Circadian rhythms are set by both genetic and environmental factors. Most people have sleep–wake and activity rhythms that, in the absence of environmental cues, are slightly longer than 24 hours, but the length of this period can be affected by circadian gene variants. Environmental factors such as light exposure, social cues, meal times, and work schedules also influence the period, phase, and amplitude of these rhythms.
Circadian rhythms emerge during early infancy but undergo various changes through the lifespan and with ageing (FIG. 2). In general, the timing of sleep onset and waking. Other biological rhythms (for example, fluctuations in melatonin levels) is earlier relative to adults during early childhood and shift later during adolescence. This shift in timing may be conserved among rodents and non-human primates (NHPs). In older adults, rhythms often return to being substantially earlier, and this shift may be accompanied by a weakening of circadian rhythms.
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)....
References: https://pmc.ncbi.nlm.nih.gov/articles/PMC6338075/
