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

In the paper

“However, on non-scheduled days, children tend to wake up later, substantially delaying their sleep–wake times, indicating that social and environmental factors, such as schedules imposed by school and parents, have a major influence on survey-based measures of chronotype9.”

What the sources say

• Disputed

  Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [9] Simpkin, C. T. et al. Chronotype is associated with the timing of the circadian clock and sleep in toddlers. J. Sleep Res. 23, 397–405 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Sleep problems are very common in children with ASD94–96, although revealing any underlying circadian abnormalities has proved difficult97,98.”

What the sources say

• Not checked yetcites [94] Cortesi, F., Giannotti, F., Ivanenko, A. & Johnson, K. Sleep in children with autistic spectrum disorder. Sleep Med. 11, 659–664 (2010). source
• Not checked yetcites [95] Richdale, A. L. & Schreck, K. A. Sleep problems in autism spectrum disorders: prevalence, nature, and possible biopsychosocial aetiologies. Sleep Med. Rev. 13, 403–411 (2009). source
• Not checked yetcites [96] Giannotti, F. et al. An investigation of sleep characteristics, EEG abnormalities and epilepsy in developmentally regressed and non-regressed children with autism. J. Autism Dev. Disord. 38, 1888–1897 (2008). source
• Supported

  The citation is attached to the difficulty of finding underlying circadian abnormalities, not to the preceding claim about how common sleep problems are. In the Results, only one child showed a tendency toward non-24-hour sleep–wake syndrome, while the others showed no tendency toward the listed rhythm disorders; the Discussion says the sleep–wake rhythm was little disturbed. These findings support the citing sentence’s cautious paraphrase. (LLM, conf=0.86)

  cites [97] Takase, M., Taira, M. & Sasaki, H. Sleep–wake rhythm of autistic children. Psychiatry Clin. Neurosci. 52, 181–182 (1998). source
• Not checked yetcites [98] Hayashi, E. Seasonal changes in sleep and behavioral problems in a pubescent case with autism. Psychiatry Clin. Neurosci. 55, 223–224 (2001). source

In the paper

“Intriguingly, activation of the epigenetically silenced paternal Ube3a allele restores neuronal circadian function127, suggesting that targeting the locus may be useful for treatment and involve molecular-clock-dependent mechanisms.”

What the sources say

• Supported

  The Results section reports that topotecan, used to reactivate the silenced paternal Ube3a allele, restored circadian period and prevented accelerated rhythm damping in Angelman-syndrome-model SCN slices. The Discussion links Ube3a to the core clock protein BMAL1 and describes paternal-allele unsilencing as a potential treatment; it does not claim an established clinical benefit. (LLM, conf=0.92)

  cites [127] Shi, S. Q., Bichell, T. J., Ihrie, R. A. & Johnson, C. H. Ube3a imprinting impairs circadian robustness in Angelman syndrome models. Curr. Biol. 25, 537–545 (2015). source

In the paper

“These changes include increases in synaptic pruning and myelination107,171, as well as increases in the availability of dopamine in the limbic circuitry172,173.”

What the sources say

• Not checked yetcites [107] Hoel, E. P., Albantakis, L., Cirelli, C. & Tononi, G. Synaptic refinement during development and its effect on slow-wave activity: a computational study. J. Neurophysiol. 115, 2199–2213 (2016). source
• Not checked yetcites [171] Frischknecht, R. & Gundelfinger, E. D. The brain’s extracellular matrix and its role in synaptic plasticity. Adv. Exp. Med. Biol. 970, 153–171 (2012). source
• Partly supported

  The ‘Adolescent Changes in the Dopamine System’ section reports peaks in dopamine tissue concentrations during adolescence and hypothesizes an increase in tonic dopamine. It does not establish increased dopamine availability specifically in limbic circuitry; the ‘Implications for Executive Control’ section says evidence for increased dopamine release or extracellular concentrations is still needed. The pruning and myelination clause carries different citations and is not assessed here. (LLM, conf=0.84)

  cites [172] Luciana, M. & Collins, P. F. Incentive motivation, cognitive control, and the adolescent brain: is it time for a paradigm shift? Child Dev. Perspect. 6, 392–399 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Dopamine section (page unavailable) reports peaks in tonic dopamine during adolescence and an increase in striatal dopamine until adolescence, supporting a developmental increase in some dopamine measures. It does not establish a general increase in dopamine availability throughout limbic circuitry: it also reports one study finding lower extracellular dopamine in the nucleus accumbens during adolescence than adulthood. The pruning and myelination clause carries different citations and is not the part judged here. (LLM, conf=0.85)

  cites [173] Padmanabhan, A. & Luna, B. Developmental imaging genetics: linking dopamine function to adolescent behavior. Brain Cogn. 89, 27–38 (2014). sourceExperimental — accuracy not yet measured

In the paper

“circadian disruptions in adolescents who are at high risk of psychosis (that is, subthreshold symptoms of psychosis, social impairment and higher suspicion–paranoia)197 and individuals with mood disorders predict worse prognosis and symptoms in longitudinal studies198,199”

What the sources say

• Not checked yetcites [197] Addington, J. & Heinssen, R. Prediction and prevention of psychosis in youth at clinical high risk. Annu. Rev. Clin. Psychol. 8, 269–289 (2012). source
• Supported

  The Results (§3.4; page not supplied) report that baseline circadian disruptions in adolescents at clinical high risk for psychosis predicted greater psychosis symptom severity and poorer psychosocial functioning at one year. This citation supports the high-risk-adolescent finding; the citing sentence assigns the mood-disorder finding to citations 198 and 199. (LLM, conf=0.92)

  cites [198] Lunsford-Avery, J. R. et al. Adolescents at clinical-high risk for psychosis: circadian rhythm disturbances predict worsened prognosis at 1-year follow-up. Schizophr. Res. 189, 37–42 (2017). source
• Not checked yetcites [199] Robillard, R. et al. Sleep–wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders. J. Sleep Res. 25, 549–555 (2016). source

In the paper

“the incidence of single-nucleotide polymorphisms (SNPs) in CLOCK and BMAL1, and in BMAL1 and PER1, are associated with increased risk of Alzheimer disease (AD) and Parkinson disease (PD), respectively251–253”

What the sources say

• Not checked yetcites [251] Chen, H. F., Huang, C. Q., You, C., Wang, Z. R. & Si-qing, H. Polymorphism of CLOCK gene rs 4580704C>G is associated with susceptibility of Alzheimer’s disease in a Chinese population. Arch. Med. Res. 44, 203–207 (2013). source
• Partly supported

  The Discussion reports that CLOCK and BMAL1 polymorphisms were associated with increased Alzheimer disease risk in the Chinese sample, particularly among APOE e4 non-carriers; it found no BMAL1 association among APOE e4 carriers. The paper does not address the claimed association of BMAL1 and PER1 polymorphisms with Parkinson disease. Page numbers were not supplied for these passages. (LLM, conf=0.88)

  cites [252] Chen, Q., Peng, X. D., Huang, C. Q., Hu, X. Y. & Zhang, X. M. Association between ARNTL (BMAL1) rs2278749 polymorphism T>C and susceptibility to Alzheimer disease in a Chinese population. Genet. Mol. Res. 14, 18515–18522 (2015). sourceExperimental — accuracy not yet measured
• Not checked yetcites [253] Gu, Z. et al. Association of ARNTL and PER1 genes with Parkinson’s disease: a case-control study of Han Chinese. Sci. Rep. 5, 15891 (2015).

In the paper

“In individuals with PD, these sleep–wake symptoms often precede the development of motor or cognitive symptoms and may even be useful as a diagnostic biomarker259,260”

What the sources say

• Partly supported

  The RBD section (page unavailable) says REM sleep behavior disorder can precede PD and may help identify a synuclein disorder; it also links RBD in PD to later cognitive dysfunction. But it specifies that only some patients have RBD before PD and many develop it during the disease, so it does not support saying that sleep–wake symptoms generally often precede motor or cognitive symptoms. (LLM, conf=0.88)

  cites [259] Claassen, D. O. & Kutscher, S. J. Sleep disturbances in Parkinson’s disease patients and management options. Nat. Sci. Sleep 3, 125–133 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and ‘Clinical Studies of Sleep Disturbance in PD’ say that sleep disturbances can precede PD motor symptoms and may help predict PD onset. They do not establish that sleep–wake symptoms precede cognitive symptoms in individuals with PD. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  cites [260] Rothman, S. M. & Mattson, M. P. Sleep disturbances in Alzheimer’s and Parkinson’s diseases. Neuromolecular Med. 14, 194–204 (2012). sourceExperimental — accuracy not yet measured

In the paper

“circadian genes in other brain regions outside of this central pace-maker also contribute locally to the control of neuronal metabolism, neurotransmitter synthesis and activity, and the disruption of these functions might contribute to brain disorders264,304–315”

What the sources say

• Supported

  The Discussion (page not available) describes CLOCK-dependent regulation of tyrosine hydroxylase in the ventral tegmental area, metabolic-clock coupling, and SIRT1 effects on dopamine-neuron firing. It also links disruption of these mechanisms to cocaine reward and notes possible implications for psychiatric disorders. The paper therefore supports this broad, hedged claim about local effects outside the SCN. (LLM, conf=0.88)

  cites [264] Logan, R. W. et al. NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward. Mol. Psychiatry. https://doi.org/10.1038/s41380-018-0061-1 (2018). This study demonstrates mechanistic links between circadian regulation of SIRT1-dependent metabolic signalling and dopaminergic neurotransmission in the mouse ventral tegmental area, which is important for drug reward. source
• Partly supported

  The Introduction and Discussion (page unavailable in our copy) show that CLOCK regulates expression of the neurotransmitter Cck in the ventral tegmental area, outside the SCN. The Discussion also reports that reducing Cck there produces manic-like behavior. These passages support a local link between a circadian gene, neurotransmission, and disorder-related behavior, but do not address neuronal metabolism or establish the claim across other brain regions generally. (LLM, conf=0.85)

  cites [304] Arey, R. N. et al. An important role for cholecystokinin, a CLOCK target gene, in the development and treatment of manic-like behaviors. Mol. Psychiatry 19, 342–350 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on VTA dopamine cell firing (page unavailable) finds that increased firing in Clock-mutant mice persists in brain slices, suggesting local changes outside the SCN. The Introduction and Discussion (pages unavailable) link the mutation to mood-related behavior, but the paper does not establish local control of neuronal metabolism or neurotransmitter synthesis; its dopamine measurements concern levels, not synthesis. (LLM, conf=0.88)

  cites [305] Coque, L. et al. Specific role of VTA dopamine neuronal firing rates and morphology in the reversal of anxiety-related, but not depression-related behavior in the Clock∆19 mouse model of mania. Neuropsychopharmacology 36, 1478–1488 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says circadian genes are expressed in mesolimbic pathways and help regulate behaviors associated with those circuits. The Discussion links Clock disruption to altered nucleus accumbens neuronal signaling and mania-like behavior. Our copy does not establish local control of neuronal metabolism or neurotransmitter synthesis, and the mouse findings do not establish local action across brain regions outside the SCN. (LLM, conf=0.87)

  cites [306] Dzirasa, K. et al. Lithium ameliorates nucleus accumbens phase-signaling dysfunction in a genetic mouse model of mania. J. Neurosci. 30, 16314–16323 (2010). sourceExperimental — accuracy not yet measured
• Partly supported

  The Master and Peripheral Clocks section describes circadian proteins in brain regions outside the SCN, and the Abnormalities section links CLOCK activity in the VTA to dopamine synthesis, neuronal activity, and behaviors associated with mania and addiction. The Conclusions suggest that disruption of clocks in these regions could contribute to addiction. Our copy does not establish local control of neuronal metabolism, and its discussion of disorders is narrower than brain disorders generally. (LLM, conf=0.84)

  cites [307] McClung, C. A. Circadian rhythms, the mesolimbic dopaminergic circuit, and drug addiction. ScientificWorldJournal 7, 194–202 (2007). sourceExperimental — accuracy not yet measured
• Not checked yetcites [308] McClung, C. A. et al. Regulation of dopaminergic transmission and cocaine reward by the Cloc k gene. Proc. Natl Acad. Sci. USA 102, 9377–9381 (2005). source
• Partly supported

  The Introduction says circadian genes are expressed throughout the brain and that rhythm disruptions may contribute to psychiatric disease. The Results show a specific local effect outside the SCN: NPAS2 regulates dopamine-receptor expression in the nucleus accumbens and affects cocaine reward. Our copy does not establish local control of neuronal metabolism or neurotransmitter synthesis, so the full list of functions is not supported by this source. (LLM, conf=0.86)

  cites [309] Ozburn, A. R. et al. Direct regulation of diurnal Drd3 expression and cocaine reward by NPAS2. Biol. Psychiatry 77, 425–433 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) says molecular-clock elements are expressed outside the SCN and links circadian genes and rhythms to psychiatric symptoms. The Results and Discussion (pages unavailable) show that Npas2 knockdown in the nucleus accumbens alters GABAA receptor expression and inhibitory neuronal activity. The paper does not establish the claimed local control of neuronal metabolism or neurotransmitter synthesis. (LLM, conf=0.87)

  cites [310] Ozburn, A. R. et al. NPAS2 regulation of anxiety-like behavior and GABAA receptors. Front. Mol. Neurosci. 10, 360 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page not provided) links reduced Clock expression in the ventral tegmental area to changes in dopamine synthesis, metabolism and neuronal activity, and suggests these changes may affect cocaine reinforcement. This supports a local role for a circadian gene outside the SCN, but the paper does not establish the broader claim about neuronal metabolism or brain disorders generally. (LLM, conf=0.86)

  cites [311] Ozburn, A. R., Larson, E. B., Self, D. W. & McClung, C. A. Cocaine self-administration behaviors in Clock∆19 mice. Psychopharmacology 223, 169–177 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes local, SCN-autonomous molecular rhythms and links clock-gene variation to neuropsychiatric illness; the Results report rhythmic neuronal excitability outside the SCN. The paper does not establish local control of neuronal metabolism or neurotransmitter synthesis. Its Discussion also cautions that the accumbal changes observed in Clock mutants are unlikely to result from direct local transcriptional mechanisms. (LLM, conf=0.85)

  cites [312] Parekh, P. K. et al. Altered GluA1 (Gria1) function and accumbal synaptic plasticity in the Clock∆19 model of bipolar mania. Biol. Psychiatry. https://doi.org/10.1016/j.biopsych.2017.06.022 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Alterations in the rhythms of circadian gene expression are also associated with impaired spatial memory in these offspring46,47, and these memory deficits can be prevented by regularly scheduled supplementation of melatonin to the mother46.”

What the sources say

• Not checked yetcites [46] Vilches, N. et al. Gestational chronodisruption impairs hippocampal expression of NMDA receptor subunits Grin1b/Grin3a and spatial memory in the adult offspring. PLOS ONE 9, e91313 (2014). source
• Not checked yetcites [47] Voiculescu, S. E. et al. Behavioral and molecular effects of prenatal continuous light exposure in the adult rat. Brain Res. 1650, 51–59 (2016). source

In the paper

“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 cryptochr”

What the sources say

• Not checked yetcites [1] Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002). source

In the paper

“Circadian rhythms are near-24-hour oscillations found in essentially every physiological process in the human brain and body1.”

What the sources say

• Not checked yetcites [1] Reppert, S. M. & Weaver, D. R. Coordination of circadian timing in mammals. Nature 418, 935–941 (2002). source

In the paper

“In older adults, rhythms often return to being substantially earlier, and this shift may be accompanied by a weakening of circadian rhythms11,12.”

What the sources say

• Not checked yetcites [11] Chen, C. Y. et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 113, 206–211 (2015). This is the largest-scale study of circadian rhythms of gene expression in human post-mortem brain tissue, revealing age-related decline in the expression of core circadian genes and the emergence of other rhythmic pathways in older subjects. source
• Not checked yetcites [12] Cornelissen, G. & Otsuka, K. Chronobiology of aging: a mini-review. Gerontology 63, 118–128 (2017). source

In the paper

“In general, the timing of sleep onset and waking and other biological rhythms (for example, fluctuations in melatonin levels) is earlier relative to adults during early childhood8,9 and shifts later during adolescence, and this shift in timing may be conserved among rodents and non-human primates (NHPs)10.”

What the sources say

• Not checked yetcites [8] Werner, H., Lebourgeois, M. K., Geiger, A. & Jenni, O. G. Assessment of chronotype in four- to eleven-year-old children: reliability and validity of the Children’s Chronotype Questionnaire (CCTQ). Chronobiol. Int. 26, 992–1014 (2009). source
• Not checked yetcites [9] Simpkin, C. T. et al. Chronotype is associated with the timing of the circadian clock and sleep in toddlers. J. Sleep Res. 23, 397–405 (2014). source

In the paper

“Pregnant rats exposed to simulated shift-work (that is, complete reversal of the light–dark cycle every 3–4 days for several weeks) showed substantially reduced weight gain during early pregnancy and reduced fat-pad and liver weights, and also exhibited lower-amplitude rhythms of corticosterone, glucose, insulin and leptin levels41.”

What the sources say

• Not checked yetcites [41] Varcoe, T. J. et al. Characterisation of the maternal response to chronic phase shifts during gestation in the rat: implications for fetal metabolic programming. PLOS ONE 8, e53800 (2013). source

In the paper

“In humans, melatonin and dopamine receptors appear as early as gestational week 18 in the fetal SCN26–28, suggesting melatonin and dopamine may serve as the primary communicators of circadian information for the fetus29,30.”

What the sources say

• Not checked yetcites [26] Reppert, S. M. Pre-natal development of a hypothalamic biological clock. Progress Brain Res. 93, 119–131; discussion 132 (1992). source
• Not checked yetcites [27] Reppert, S. M. Interaction between the circadian clocks of mother and fetus. Ciba Found. Symp. 183, 198–207; discussion 207–111 (1995).
• Not checked yetcites [28] Reppert, S. M., Weaver, D. R. & Rivkees, S. A. Maternal communication of circadian phase to the developing mammal. Psychoneuroendocrinology 13, 63–78 (1988). source
• Not checked yetcites [29] Shearman, L. P., Zeitzer, J. & Weaver, D. R. Widespread expression of functional D1-dopamine receptors in fetal rat brain. Brain Res. Dev. Brain Res. 102, 105–115 (1997). source
• Not checked yetcites [30] Reiter, R. J., Tan, D. X., Korkmaz, A. & Rosales-Corral, S. A. Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Hum. Reprod. Update 20, 293–307 (2014). source

In the paper

“Exposing pregnant NHPs to constant light suppresses the emergence of melatonin and body temperature rhythms in their offspring following birth42–44, suggesting that maternal rhythms are important for the early brain development of fetal circadian systems45.”

What the sources say

• Not checked yetcites [42] Torres-Farfan, C. et al. Maternal melatonin selectively inhibits cortisol production in the primate fetal adrenal gland. J. Physiol. 554, 841–856 (2004). source
• Not checked yetcites [43] Seron-Ferre, M. et al. Impact of chronodisruption during primate pregnancy on the maternal and newborn temperature rhythms. PLOS ONE 8, e57710 (2013). source
• Not checked yetcites [44] Matsumoto, T. et al. Circadian myometrial and endocrine rhythms in the pregnant rhesus macaque: effects of constant light and timed melatonin infusion. Am. J. Obstet. Gynecol. 165, 1777–1784 (1991). source
• Not checked yetcites [45] Novakova, M., Sladek, M. & Sumova, A. Exposure of pregnant rats to restricted feeding schedule synchronizes the SCN clocks of their fetuses under constant light but not under a light-dark regime. J. Biol. Rhythms 25, 350–360 (2010). source

In the paper

“Melatonin from the mother readily passes through the placenta and the fetal blood–brain barrier and may thus be the predominant relay of time-of-day information to the fetus, particularly during the transition from dusk to night, as circulating melatonin rises31–34.”

What the sources say

• Not checked yetcites [31] Okatani, Y. et al. Maternal–fetal transfer of melatonin in pregnant women near term. J. Pineal Res. 25, 129–134 (1998). source
• Not checked yetcites [32] Schenker, S. et al. Antioxidant transport by the human placenta. Clin. Nutr. 17, 159–167 (1998). source
• Not checked yetcites [33] Davis, F. C. & Mannion, J. Entrainment of hamster pup circadian rhythms by prenatal melatonin injections to the mother. Am. J. Physiol. 255, R439–R448 (1988).
• Not checked yetcites [34] Seron-Ferre, M. et al. Circadian rhythms in the fetus. Mol. Cell. Endocrinol. 349, 68–75 (2012). source

In the paper

“The same manipulation also affected metabolic and circadian gene expression rhythms in the fetal liver, but did not affect placental or fetal growth41.”

What the sources say

• Not checked yetcites [41] Varcoe, T. J. et al. Characterisation of the maternal response to chronic phase shifts during gestation in the rat: implications for fetal metabolic programming. PLOS ONE 8, e53800 (2013). source

In the paper

“Notably, these effects are evident in offspring from parents exposed to dim light at night before breeding, suggesting that repeated exposure to dim light at night leads to epigenetic modifications that can be passed between generations.”

In the paper

“During the first year of life, sleep–wake rhythms continue to consolidate, coinciding with increased melatonin secretion at sunset23.”

What the sources say

• Not checked yetcites [23] Rivkees, S. A. Developing circadian rhythmicity in infants. Pediatr. Endocrinol. Rev. 1, 38–45 (2003).

In the paper

“For example, chronically exposing mice to dim light at night impairs adaptive immune function49 and increases depression-like behaviours50 in their offspring.”

What the sources say

• Not checked yetcites [49] Cisse, Y. M., Russart, K. L. & Nelson, R. J. Parental exposure to dim light at night prior to mating alters offspring adaptive immunity. Sci. Rep. 7, 45497 (2017). source
• Not checked yetcites [50] Cisse, Y. M., Russart, K. L. G. & Nelson, R. J. Depressive-like behavior is elevated among offspring of parents exposed to dim light at night prior to mating. Psychoneuroendocrinology 83, 182–186 (2017). source

In the paper

“Reductions in sleep quality, delays in circadian phase and evening preference are consistently reported in children and adults with ADHD87 and may be correlated with the severity of ADHD symptoms88.”

What the sources say

• Not checked yetcites [87] Coogan, A. N. & McGowan, N. M. A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Atten. Defic. Hyperact. Disord. 9, 129–147 (2017). source
• Not checked yetcites [88] Rybak, Y. E., McNeely, H. E., Mackenzie, B. E., Jain, U. R. & Levitan, R. D. Seasonality and circadian preference in adult attention-deficit/hyperactivity disorder: clinical and neuropsychological correlates. Compr. Psychiatry 48, 562–571 (2007). source

In the paper

“Temperature rhythms appear almost immediately after birth in full-term infants, whereas other rhythms, including rest–activity, sleep–wake and hormonal cycles, typically develop between 3 and 6 months of age23,52.”

What the sources say

• Not checked yetcites [23] Rivkees, S. A. Developing circadian rhythmicity in infants. Pediatr. Endocrinol. Rev. 1, 38–45 (2003).
• Not checked yetcites [52] Kennaway, D. J., Stamp, G. E. & Goble, F. C. Development of melatonin production in infants and the impact of prematurity. J. Clin. Endocrinol. Metab. 75, 367–369 (1992).

In the paper

“PWS is also accompanied by shorter sleep duration and excessive daytime sleepiness71,111,112.”

What the sources say

• Not checked yetcites [71] Guyer, C. et al. Very preterm infants show earlier emergence of 24-hour sleep-wake rhythms compared to term infants. Early Hum. Dev. 91, 37–42 (2015). source
• Not checked yetcites [111] Lassi, G. et al. Deletion of the Snord116/SNORD116 alters sleep in mice and patients with Prader–Willi syndrome. Sleep 39, 637–644 (2016). source
• Not checked yetcites [112] Butler, J. V. et al. Prevalence of, and risk factors for, physical ill-health in people with Prader–Willi syndrome: a population-based study. Dev. Med. Child Neurol. 44, 248–255 (2002).

In the paper

“One of the most common neurodevelopmental disorders of childhood, ADHD, is characterized by inattentiveness, impulsivity and hyperactivity and is associated with high rates of co-occurring sleep problems and circadian alterations86.”

What the sources say

• Not checked yetcites [86] Philipsen, A., Hornyak, M. & Riemann, D. Sleep and sleep disorders in adults with attention deficit/hyperactivity disorder. Sleep Med. Rev. 10, 399–405 (2006). source

In the paper

“Variants identified in the promoter of the ASMT gene were specific to individuals with ASD compared with controls and were associated with reduced ASMT activity and melatonin levels102.”

What the sources say

• Not checked yetcites [102] Melke, J. et al. Abnormal melatonin synthesis in autism spectrum disorders. Mol. Psychiatry 13, 90–98 (2008). source

In the paper

“Premature infants kept in regular light–dark conditions also fed orally sooner and spent fewer days on ventilator assistance, but had similar motor coordination compared with infants under continuous near darkness in the NICU (28–32 weeks of gestation)79–85.”

What the sources say

• Not checked yetcites [79] Boo, N. Y., Chee, S. C. & Rohana, J. Randomized controlled study of the effects of different durations of light exposure on weight gain by preterm infants in a neonatal intensive care unit. Acta Paediatr. 91, 674–679 (2002). source
• Not checked yetcites [80] Brandon, D. H., Holditch-Davis, D. & Belyea, M. Preterm infants born at less than 31 weeks’ gestation have improved growth in cycled light compared with continuous near darkness. J. Pediatr. 140, 192–199 (2002). This randomized intervention study reports that preterm infants (<31 weeks) receiving cycled light (11 hours on and 11 hours off, with 1 transition hour for shift changes) during hospital care (~4 weeks) gained weight faster than age-matched infants receiving near darkness. source
• Not checked yetcites [81] Guyer, C. et al. Cycled light exposure reduces fussing and crying in very preterm infants. Pediatrics 130, e145–e151 (2012). source
• Not checked yetcites [82] Hao, H. & Rivkees, S. A. The biological clock of very premature primate infants is responsive to light. Proc. Natl Acad. Sci. USA 96, 2426–2429 (1999). source
• Not checked yetcites [83] Lebel, V., Aita, M., Johnston, C., Heon, M. & Dupuis, F. Effects of cycled lighting versus continuous near darkness on physiological stability and motor activity level in preterm infants. Adv. Neonatal Care 17, 282–291 (2017). source
• Not checked yetcites [84] Mann, N. P., Haddow, R., Stokes, L., Goodley, S. & Rutter, N. Effect of night and day on preterm infants in a newborn nursery: randomised trial. Br. Med. J. (Clin. Res. Ed.) 293, (1265–1267 (1986).
• Not checked yetcites [85] Rivkees, S. A., Mayes, L., Jacobs, H. & Gross, I. Rest-activity patterns of premature infants are regulated by cycled lighting. Pediatrics 113, 833–839 (2004). source

In the paper

“Early-morning light exposure (between 03:00 h and 04:00 h) also reduced melatonin, although no differences were found between early and late adolescents145.”

What the sources say

• Not checked yetcites [145] Crowley, S. J., Cain, S. W., Burns, A. C., Acebo, C. & Carskadon, M. A. Increased sensitivity of the circadian system to light in early/mid-puberty. J. Clin. Endocrinol. Metab. 100, 4067–4073 (2015). This study shows that endogenous melatonin levels of prepubertal children and early adolescents are more sensitive to the suppressive effects of acute light exposure during the evening than melatonin levels in late adolescents. source

In the paper

“For example, SNORD116 is expressed exclusively from the paternally inherited allele113, whereas maternally inherited alleles of UBE3A are linked to PWS119,120.”

What the sources say

• Not checked yetcites [113] Cavaille, J. et al. Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization. Proc. Natl Acad. Sci. USA 97, 14311–14316 (2000). source
• Not checked yetcites [119] Martins-Taylor, K. et al. Imprinted expression of UBE3A in non-neuronal cells from a Prader–Willi syndrome patient with an atypical deletion. Hum. Mol. Genet. 23, 2364–2373 (2014). source
• Not checked yetcites [120] Rougeulle, C., Glatt, H. & Lalande, M. The Angelman syndrome candidate gene, UBE3A/E6-AP, is imprinted in brain. Nat. Genet. 17, 14–15 (1997). source

In the paper

“Maternal duplications of the 15q11–13 locus lead to increased expression of UBE3A and epigenetic silencing of the paternal antisense transcript, UBE3A-ATS121–124.”

What the sources say

• Not checked yetcites [121] Baron, C. A. et al. Genomic and functional profiling of duplicated chromosome 15 cell lines reveal regulatory alterations in UBE3A-associated ubiquitin-proteasome pathway processes. Hum. Mol. Genet. 15, 853–869 (2006). source
• Not checked yetcites [122] Herzing, L. B., Cook, E. H. Jr & Ledbetter, D. H. Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11-q13 duplications. Hum. Mol. Genet. 11, 1707–1718 (2002). source
• Not checked yetcites [123] Hogart, A. et al. Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J. Med. Genet. 46, 86–93 (2009). source
• Not checked yetcites [124] Nishimura, Y. et al. Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum. Mol. Genet. 16, 1682–1698 (2007). source

In the paper

“Circadian disruptions (such as social jet-lag) during adolescence increase vulnerability to substance use, and conversely, chronic exposure to these substances can lead to long-lasting changes in the circadian and sleep networks154.”

What the sources say

• Not checked yetcites [154] Falcon, E. & McClung, C. A. A role for the circadian genes in drug addiction. Neuropharmacology 56, 91–96 (2009). (Suppl. 1). source

In the paper

“Mice with a heterozygous deletion of Rai1 display a shortened locomotor activity period133,134, although these mice are of mixed genetic background containing C57BL/6, which do not produce pineal melatonin.”

What the sources say

• Not checked yetcites [133] Walz, K. et al. Behavioral characterization of mouse models for Smith–Magenis syndrome and dup(17)(p11.2p11.2). Hum. Mol. Genet. 13, 367–378 (2004). source
• Not checked yetcites [134] Lacaria, M., Gu, W. & Lupski, J. R. Circadian abnormalities in mouse models of Smith–Magenis syndrome: evidence for involvement of RAI1. Am. J. Med. Genet. A 161A, 1561–1568 (2013). source

In the paper

“Thus, therapies targeting the reversal of melatonin rhythms in patients with SMS may improve sleep, as well as behaviour, attention and learning137–139.”

What the sources say

• Not checked yetcites [137] De Leersnyder, H. et al. β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith–Magenis syndrome. J. Med. Genet. 40, 74–78 (2003). source
• Not checked yetcites [138] De Leersnyder, H., Claustrat, B., Munnich, A. & Verloes, A. Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome. Mol. Cell Endocrinol. 252, 88–91 (2006). source
• Not checked yetcites [139] Elsea, S. H. & Girirajan, S. Smith–Magenis syndrome. Eur. J. Hum. Genet. 16, 412–421 (2008). source

In the paper

“Moreover, adolescents with shorter sleep duration are more likely to use substances, including caffeine, nicotine, alcohol and marijuana157–159, and to engage in other risky behaviours157,160,161.”

What the sources say

• Not checked yetcites [157] McKnight-Eily, L. R. et al. Relationships between hours of sleep and health-risk behaviors in US adolescent students. Prev. Med. 53, 271–273 (2011). source
• Not checked yetcites [158] Paiva, T., Gaspar, T. & Matos, M. G. Mutual relations between sleep deprivation, sleep stealers and risk behaviours in adolescents. Sleep Sci. 9, 7–13 (2016). source
• Not checked yetcites [159] Sivertsen, B., Skogen, J. C., Jakobsen, R. & Hysing, M. Sleep and use of alcohol and drug in adolescence. A large population-based study of Norwegian adolescents aged 16 to 19 years. Drug Alcohol Depend. 149, 180–186 (2015). source
• Not checked yetcites [160] Thomas, A. G., Monahan, K. C., Lukowski, A. F. & Cauffman, E. Sleep problems across development: a pathway to adolescent risk taking through working memory. J. Youth Adolesc. 44, 447–464 (2015). source
• Not checked yetcites [161] Wheaton, A. G., Olsen, E. O., Miller, G. F. & Croft, J. B. Sleep duration and injury-related risk behaviors among high school students — United States, 2007–2013. MMWR Morb. Mortal. Wkly Rep. 65, 337–341 (2016). source

In the paper

“At the onset of puberty, sleep–wake cycles and melatonin rhythms start to phase delay141 — a shift that is dependent on the presence of gonadal hormones, and that coincides with sexual maturity142,143.”

What the sources say

• Not checked yetcites [141] Roenneberg, T. et al. A marker for the end of adolescence. Curr. Biol. 14, R1038–R1039 (2004). source
• Not checked yetcites [142] Hagenauer, M. H. & Lee, T. M. The neuroendocrine control of the circadian system: adolescent chronotype. Front. Neuroendocrinol. 33, 211–229 (2012). source
• Not checked yetcites [143] Hagenauer, M. H. & Lee, T. M. Adolescent sleep patterns in humans and laboratory animals. Horm. Behav. 64, 270–279 (2013). source

In the paper

“Combining β1-adrenergic receptor antagonism with timed administration of exogenous melatonin greatly improves sleep (that is, leading to fewer sleep awakenings and better organized sleep stages) and also reduces disruptive behaviours during the daytime in children and adolescents with SMS137.”

What the sources say

• Not checked yetcites [137] De Leersnyder, H. et al. β1-adrenergic antagonists and melatonin reset the clock and restore sleep in a circadian disorder, Smith–Magenis syndrome. J. Med. Genet. 40, 74–78 (2003). source

In the paper

“For example, light exposure during the night (23:00 h to 24:00 h) suppresses melatonin levels in adolescents, with greater suppression occurring in early adolescents (prepubertal to mid-pubertal adolescents aged 9–14 years) than in late adolescents (aged 11–15 years, in late pubertal to post-pubertal stages)145.”

What the sources say

• Not checked yetcites [145] Crowley, S. J., Cain, S. W., Burns, A. C., Acebo, C. & Carskadon, M. A. Increased sensitivity of the circadian system to light in early/mid-puberty. J. Clin. Endocrinol. Metab. 100, 4067–4073 (2015). This study shows that endogenous melatonin levels of prepubertal children and early adolescents are more sensitive to the suppressive effects of acute light exposure during the evening than melatonin levels in late adolescents. source

In the paper

“Symptoms of SMS also include sleep and circadian abnormalities, with the most extreme being a complete reversal of sleep–wake patterns (that is, daytime sleep and night-time wake)128–131.”

What the sources say

• Not checked yetcites [128] Boudreau, E. A. et al. Review of disrupted sleep patterns in Smith–Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion. Am. J. Med. Genet. A 149A, 1382–1391 (2009). source
• Not checked yetcites [129] Greenberg, F. et al. Multi-disciplinary clinical study of Smith–Magenis syndrome (deletion 17p11.2). Am. J. Med. Genet. 62, 247–254 (1996). source
• Not checked yetcites [130] Gropman, A. L., Elsea, S., Duncan, W. C. Jr & Smith, A. C. New developments in Smith–Magenis syndrome (del 17p11.2). Curr. Opin. Neurol. 20, 125–134 (2007). source
• Not checked yetcites [131] Smith, A. C., Dykens, E. & Greenberg, F. Sleep disturbance in Smith–Magenis syndrome (del 17p11.2). Am. J. Med. Genet. 81, 186–191 (1998). source

In the paper

“In human cells from patients with SMS and the mouse brain, RAI1 activates the transcription of CLOCK via direct binding to enhancer elements within intron 1 of the CLOCK gene135, demonstrating a possible mechanism by which loss of RAI1 may result in circadian dysfunction at the molecular and cellular level.”

What the sources say

• Not checked yetcites [135] Williams, S. R., Zies, D., Mullegama, S. V., Grotewiel, M. S. & Elsea, S. H. Smith–Magenis syndrome results in disruption of CLOCK gene transcription and reveals an integral role for RAI1 in the maintenance of circadian rhythmicity. Am. J. Hum. Genet. 90, 941–949 (2012). source

In the paper

“RAI1 is implicated in melatonin secretion, and inverted melatonin rhythms may be responsible for these sleep disturbances132.”

What the sources say

• Not checked yetcites [132] Boone, P. M. et al. Abnormal circadian rhythm of melatonin in Smith–Magenis syndrome patients with RAI 1 point mutations. Am. J. Med. Genet. A 155A, 2024–2027 (2011). source

In the paper

“Weekday–weekend differences in sleep timing and duration are associated with increased risk-taking behaviours, substance use and depressed mood155,156.”

What the sources say

• Not checked yetcites [155] O’Brien, E. M. & Mindell, J. A. Sleep and risk-taking behavior in adolescents. Behav. Sleep Med. 3, 113–133 (2005). source
• Not checked yetcites [156] Pasch, K. E., Laska, M. N., Lytle, L. A. & Moe, S. G. Adolescent sleep, risk behaviors, and depressive symptoms: are they linked? Am. J. Health Behav. 34, 237–248 (2010). source

In the paper

“UBE3A targets the circadian transcription factor BMAL1 for proteasomal degradation and thus is crucial for maintaining the pace of molecular clock timing117.”

What the sources say

• Not checked yetcites [117] Gossan, N. C. et al. The E3 ubiquitin ligase UBE3A is an integral component of the molecular circadian clock through regulating the BMAL1 transcription factor. Nucleic Acids Res. 42, 5765–5775 (2014). source

In the paper

“Longitudinal follow-up studies have found that weekend delay and sleep-timing variability during adolescence and young adulthood positively correlate with alcohol use 2 years later162 and the incidence of alcohol use disorder symptoms 3 and 5 years later163 and are associated with an earlier onset of alcohol use disorder164.”

What the sources say

• Not checked yetcites [162] Pasch, K. E., Latimer, L. A., Cance, J. D., Moe, S. G. & Lytle, L. A. Longitudinal bi-directional relationships between sleep and youth substance use. J. Youth Adolesc. 41, 1184–1196 (2012). source
• Not checked yetcites [163] Hasler, B. P., Martin, C. S., Wood, D. S., Rosario, B. & Clark, D. B. A longitudinal study of insomnia and other sleep complaints in adolescents with and without alcohol use disorders. Alcohol Clin. Exp. Res. 38, 2225–2233 (2014). source
• Not checked yetcites [164] Hasler, B. P., Kirisci, L. & Clark, D. B. Restless sleep and variable sleep timing during late childhood accelerate the onset of alcohol and other drug involvement. J. Stud. Alcohol Drugs 77, 649–655 (2016). source

In the paper

“Functional MRI studies reveal that the activation (that is, glucose uptake) of striatal and prefrontal brain regions during monetary reward tasks is greater in the afternoon or evening than in the morning in late adolescents and young adults (aged 19–24 years)177, and is related to morningness and eveningness chronotypes in adults178.”

What the sources say

• Not checked yetcites [177] Hasler, B. P., Forbes, E. E. & Franzen, P. L. Time-of-day differences and short-term stability of the neural response to monetary reward: a pilot study. Psychiatry Res. 224, 22–27 (2014). source
• Not checked yetcites [178] Hasler, B. P. et al. Chronotype and diurnal patterns of positive affect and affective neural circuitry in primary insomnia. J. Sleep Res. 21, 515–526 (2012). source

In the paper

“these disorders are very heterogeneous, and any association with disruptions in the sleep–wake cycle can be highly variable from individual to individual”

In the paper

“Together, these findings suggest that circadian and sleep disruptions may have a role in the vulnerability to mood disorders and the precipitation of disorder symptoms.”

In the paper

“Behavioural (but not pharmacological) interventions for insomnia improved sleep quality and reduced symptoms of depression”

What the sources say

• Not checked yetcites [181] Miller, M. B., Donahue, M. L., Carey, K. B. & Scott-Sheldon, L. A. J. Insomnia treatment in the context of alcohol use disorder: a systematic review and meta-analysis. Drug Alcohol Depend. 181, 200–207 (2017). source

In the paper

“In an age-matched cohort of late adolescents, greater VS responses to reward outcome and reduced mPFC responses to reward anticipation are associated with eveningness179 and may predict alcohol dependence167, further suggesting that certain circadian phenotypes emerging during early to late adolescence could contribute to vulnerability to substance use.”

What the sources say

• Not checked yetcites [179] Hasler, B. P., Sitnick, S. L., Shaw, D. S. & Forbes, E. E. An altered neural response to reward may contribute to alcohol problems among late adolescents with an evening chronotype. Psychiatry Res. 214, 357–364 (2013). source
• Not checked yetcites [167] Hasler, B. P., Casement, M. D., Sitnick, S. L., Shaw, D. S. & Forbes, E. E. Eveningness among late adolescent males predicts neural reactivity to reward and alcohol dependence two years later. Behav. Brain Res. 327, 112–120 (2017). This study shows that an evening chronotype during late adolescence (20 years of age) is associated with strength of activation in the VS to reward outcome, which was positively correlated with alcohol dependence 2 years later. source

In the paper

“Many of these selective synaptic pruning and refinement processes occur during sleep, and sleep is crucial for proper circuit maturation and long-term memory formation in humans and animals201–204.”

What the sources say

• Not checked yetcites [201] Wei, Y., Krishnan, G. P. & Bazhenov, M. Synaptic mechanisms of memory consolidation during sleep slow oscillations. J. Neurosci. 36, 4231–4247 (2016). source
• Not checked yetcites [202] Walker, M. P. & Stickgold, R. Sleep-dependent learning and memory consolidation. Neuron 44, 121–133 (2004). source
• Not checked yetcites [203] Havekes, R., Meerlo, P. & Abel, T. Animal studies on the role of sleep in memory: from behavioral performance to molecular mechanisms. Curr. Top. Behav. Neurosci. 25, 183–206 (2015). source
• Not checked yetcites [204] Marshall, L., Helgadottir, H., Molle, M. & Born, J. Boosting slow oscillations during sleep potentiates memory. Nature 444, 610–613 (2006). This study establishes the importance of slow-wave sleep during non-REM episodes that occur during the early night and shows that it promotes the retention of hippocampus-dependent declarative memories. source

In the paper

“Several studies have reported declines in melatonin levels with ageing, although others find no difference compared with younger people in a healthy population237,238.”

What the sources say

• Not checked yetcites [237] Karasek, M. Melatonin, human aging, and age-related diseases. Exp. Gerontol. 39, 1723–1729 (2004). source
• Not checked yetcites [238] Zeitzer, J. M. et al. Do plasma melatonin concentrations decline with age? Am. J. Med. 107, 432–436 (1999). source

In the paper

“older individuals show lower-amplitude body temperature rhythms, with the minimum of the endogenous phase occurring nearly 2 hours earlier than in younger individuals239”

What the sources say

• Not checked yetcites [239] Czeisler, C. A. et al. Association of sleep–wake habits in older people with changes in output of circadian pacemaker. Lancet 340, 933–936 (1992). This landmark study suggests that changes in sleep timing and consolidation driven by the circadian system underlie sleep disturbances in elderly individuals. source

In the paper

“Compared with healthy aged people, individuals with AD or PD show considerably lower melatonin rhythm amplitudes and excessive sleepiness, as well as other sleep–wake cycle disturbances, such as later sleep onsets254–258.”

What the sources say

• Not checked yetcites [254] Videnovic, A. & Golombek, D. Circadian dysregulation in Parkinson’s disease. Neurobiol. Sleep Circadian Rhythms 2, 53–58 (2017). source
• Not checked yetcites [255] Breen, D. P. et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 71, 589–595 (2014). This study shows significantly increased sleep latency, reduced sleep efficiency and reduced REM, along with reduced melatonin levels and a loss of BMAL1 serum expression rhythms, in a cohort of 239 individuals with PD. source
• Not checked yetcites [256] Gros, P. & Videnovic, A. Sleep and circadian rhythm disorders in Parkinson’s disease. Curr. Sleep Med. Rep. 3, 222–234 (2017). source
• Not checked yetcites [257] Uchida, K., Okamoto, N., Ohara, K. & Morita, Y. Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res. 717, 154–159 (1996). source
• Not checked yetcites [258] Videnovic, A. et al. Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol. 71, 463–469 (2014). source

In the paper

“These rhythmic genes might be protective, as the individuals in this post-mortem study did not experience psychiatric or neurodegenerative disorders before death.”

In the paper

“Older people (ages ~65 years and older) generally sleep less and have poorer sleep efficiency, increased night-time awakening, increased sleep latency and greater levels of daytime sleepiness234–236.”

What the sources say

• Not checked yetcites [234] Feinsilver, S. H. & Hernandez, A. B. Sleep in the elderly: unanswered questions. Clin. Geriatr. Med. 33, 579–596 (2017). source
• Not checked yetcites [235] Mattis, J. & Sehgal, A. Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol. Metab. 27, 192–203 (2016). source
• Not checked yetcites [236] Musiek, E. S. & Holtzman, D. M. Mechanisms linking circadian clocks, sleep, and neurodegeneration. Science 354, 1004–1008 (2016). source

In the paper

“Shift-work has been associated with increased risk of cancer, obesity, heart disease, gastrointestinal dysfunction, sleep disorders, diabetes and depression227.”

What the sources say

• Not checked yetcites [227] James, S. M., Honn, K. A., Gaddameedhi, S. & Van Dongen, H. P. A. Shift work: disrupted circadian rhythms and sleep-implications for health and well-being. Curr. Sleep Med. Rep. 3, 104–112 (2017). source

In the paper

“Another study of ~14,000 workers in electronics manufacturing in South Korea revealed that, compared with daytime workers, shift-workers showed higher rates of insomnia, depression and suicidal ideation (with the strongest association with insomnia)229.”

What the sources say

• Not checked yetcites [229] Kang, M. Y., Kwon, H. J., Choi, K. H., Kang, C. W. & Kim, H. The relationship between shift work and mental health among electronics workers in South Korea: a cross-sectional study. PLOS ONE 12, e0188019 (2017).

In the paper

“These SCN network changes result in desynchronization and a reduction in the amplitude of neuronal activity rhythms248,249 and, ultimately, physiological and behavioural rhythms241.”

What the sources say

• Not checked yetcites [248] Farajnia, S. et al. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J. Neurosci. 32, 5891–5899 (2012). source
• Not checked yetcites [249] Nakamura, T. J. et al. Age-related decline in circadian output. J. Neurosci. 31, 10201–10205 (2011). source
• Not checked yetcites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

In the paper

“some SCN cells become silent in older animals (as measured in vitro), and SCN neurons lose phase coherence with age247,248”

What the sources say

• Not checked yetcites [247] Nygard, M., Hill, R. H., Wikstrom, M. A. & Kristensson, K. Age-related changes in electrophysiological properties of the mouse suprachiasmatic nucleus in vitro. Brain Res. Bull. 65, 149–154 (2005). source
• Not checked yetcites [248] Farajnia, S. et al. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J. Neurosci. 32, 5891–5899 (2012). source

In the paper

“gene expression rhythms in the human mPFC also decline with age; however, surprisingly, a separate set of genes becomes newly rhythmic in older people (aged 65 years and older)11”

What the sources say

• Not checked yetcites [11] Chen, C. Y. et al. Effects of aging on circadian patterns of gene expression in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 113, 206–211 (2015). This is the largest-scale study of circadian rhythms of gene expression in human post-mortem brain tissue, revealing age-related decline in the expression of core circadian genes and the emergence of other rhythmic pathways in older subjects. source

In the paper

“these sex differences disappear after the age of 50 years, coinciding with menopause in women141,220,222”

What the sources say

• Not checked yetcites [141] Roenneberg, T. et al. A marker for the end of adolescence. Curr. Biol. 14, R1038–R1039 (2004). source
• Not checked yetcites [220] Adan, A. & Natale, V. Gender differences in morningness–eveningness preference. Chronobiol. Int. 19, 709–720 (2002). source
• Not checked yetcites [222] Duarte, L. L. et al. Chronotype ontogeny related to gender. Braz. J. Med. Biol. Res. 47, 316–320 (2014). source

In the paper

“these measures of chronotype are also affected by social and work schedules, and some individuals may never shift back to a morning preference after adolescence223”

What the sources say

• Not checked yetcites [223] Paine, S. J., Gander, P. H. & Travier, N. The epidemiology of morningness/eveningness: influence of age, gender, ethnicity, and socioeconomic factors in adults (30–49 years). J. Biol. Rhythms 21, 68–76 (2006). source

In the paper

“Female flight attendants also have a higher prevalence of reproductive cancers, skin cancers and other conditions such as chronic bronchitis and heart disease230,231”

What the sources say

• Not checked yetcites [230] McNeely, E. et al. The self-reported health of U. S. flight attendants compared to the general population. Environ. Health 13, 13 (2014). source
• Not checked yetcites [231] McNeely, E. et al. Cancer prevalence among flight attendants compared to the general population. Environ. Health 17, 49 (2018). source

In the paper

“brain-specific knockout of Sirt1 in rodents is sufficient to phenocopy the effects of ageing on the SCN and circadian behaviour, whereas overexpression of Sirt1 is protective241”

What the sources say

• Not checked yetcites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

In the paper

“Sundowning syndrome is prevalent in people with dementia and is characterized by increases in aggression, restlessness, delirium and agitation specifically in the late afternoon or early evening280,281.”

What the sources say

• Not checked yetcites [280] Gnanasekaran, G. “Sundowning” as a biological phenomenon: current understandings and future directions: an update. Aging Clin. Exp. Res. 28, 383–392 (2016). source
• Not checked yetcites [281] Bedrosian, T. A. & Nelson, R. J. Sundowning syndrome in aging and dementia: research in mouse models. Exp. Neurol. 243, 67–73 (2013). source

In the paper

“In mice, SCN levels of sirtuin 1 (SIRT1), a metabolic sensing protein and mediator of CLOCK and BMAL1 function (FIG. 1), decline with age, potentially explaining the increase in circadian rhythm disruptions in older people241.”

What the sources say

• Not checked yetcites [241] Chang, H. C. & Guarente, L. SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell 153, 1448–1460 (2013). This mouse study reveals that reductions of sirtuin activity in the SCN leads to a gradual age-dependent dampening of SCN activity and locomotor rhythms. source

In the paper

“during sleep, the glymphatic system285 exchanges cerebrospinal fluid with interstitial fluid and clears Aβ286”

What the sources say

• Not checked yetcites [285] Xie, L. et al. Sleep drives metabolite clearance from the adult brain. Science 342, 373–377 (2013). A landmark study in mice demonstrating that wakefulness suppresses the outflow of cerebral spinal fluid from the brain, whereas sleep leads to an increase in convective fluxes of fluid, effectively promoting the clearance of neurotoxic metabolics, including Aβ. source
• Not checked yetcites [286] Da Mesquita, S. et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560, 185–191 (2018). source

In the paper

“Sleep deprivation increases interstitial fluid levels of Aβ and increases plaque formation in mice and flies287,288, whereas in Drosophila, genetically increasing sleep reduces Aβ deposition288.”

What the sources say

• Not checked yetcites [287] Kang, J. E. et al. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009). source
• Not checked yetcites [288] Tabuchi, M. et al. Sleep interacts with Aβ to modulate intrinsic neuronal excitability. Curr. Biol. 25, 702–712 (2015). source

In the paper

“Phase delays and reductions in the amplitude of body temperature rhythms correlate with the severity of sundowning symptoms, suggesting that a breakdown of the circadian system may be responsible282.”

What the sources say

• Not checked yetcites [282] Volicer, L., Harper, D. G., Manning, B. C., Goldstein, R. & Satlin, A. Sundowning and circadian rhythms in Alzheimer’s disease. Am. J. Psychiatry 158, 704–711 (2001). This study shows that patients with AD have less diurnal activity, more nocturnal activity and phase delays in body-temperature rhythms, and that the severity of sundowning is positively correlated with lower-amplitude and more-phase-delayed rhythms. source

In the paper

“ROS accumulation is considerably higher in Bmal1−/− mice and correlates with increases in astrocytosis and levels of oxidative damage markers in the brain.”

What the sources say

• Not checked yetcites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

In the paper

“Bmal1−/− mice, which lack a functional molecular clock, show premature ageing, neurodegeneration and a reduced lifespan291.”

What the sources say

• Not checked yetcites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

In the paper

“SCN neuronal firing is also reduced in these mice from young adulthood and progressively worsens with age, suggesting a weakened circadian pacemaker276 and a potential loss of dopaminergic modulation of circadian rhythms via midbrain, striatal and SCN circuits277,278.”

What the sources say

• Not checked yetcites [276] Kudo, T., Loh, D. H., Truong, D., Wu, Y. & Colwell, C. S. Circadian dysfunction in a mouse model of Parkinson’s disease. Exp. Neurol. 232, 66–75 (2011). source
• Not checked yetcites [277] Grippo, R. M., Purohit, A. M., Zhang, Q., Zweifel, L. S. & Guler, A. D. Direct midbrain dopamine input to the suprachiasmatic nucleus accelerates circadian entrainment. Curr. Biol. 27, 2465–2475 (2017). This study shows re-entrainment of the SCN to phase shifts in the light–dark schedule is facilitated by dopaminergic projections from the ventral tegmental area to the SCN and is dependent on dopamine 1 receptor-expressing neurons in the SCN. source
• Not checked yetcites [278] Korshunov, K. S., Blakemore, L. J. & Trombley, P. Q. Dopamine: a modulator of circadian rhythms in the central nervous system. Front. Cell. Neurosci. 11, 91 (2017). source

In the paper

“mice with a brain-specific Bmal1 deletion also exhibit increased astrocytosis, despite having mostly normal locomotor circadian rhythms and sleep–wake cycling (that is, relatively normal clock function in the SCN); thus, these neurodegenerative effects are probably due to loss of the local control of cellular metabolism in specific regions of the brain that is normally mediated by BMAL1, indep”

What the sources say

• Not checked yetcites [291] Musiek, E. S. et al. Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration. J. Clin. Invest. 123, 5389–5400 (2013). This preclinical investigation demonstrates that components of the molecular clock control redox state and, when disrupted, lead to oxidative stress and cell death related to neurodegeneration. source

In the paper

“Transgenic mice overexpressing α-synuclein (a model of PD) show greater fragmentation and amplitude reduction in locomotor activity rhythms during the active phase, and these effects progress with age276.”

What the sources say

• Not checked yetcites [276] Kudo, T., Loh, D. H., Truong, D., Wu, Y. & Colwell, C. S. Circadian dysfunction in a mouse model of Parkinson’s disease. Exp. Neurol. 232, 66–75 (2011). source

In the paper

“These increases were negatively correlated with mood but were not associated with a particular AD-linked genotype (that is, the APOE genotype).”

What the sources say

• Not checked yetcites [284] Shokri-Kojori, E. et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc. Natl Acad. Sci. USA 115, 4483–4488 (2018). source

In the paper

“based on estimates of anatomical and fluid dynamic parameters, the plausibility of periarterial flow and glymphatic circulation is controversial”

What the sources say

• Not checked yetcites [289] Faghih, M. M. & Sharp, M. K. Is bulk flow plausible in perivascular, paravascular and paravenous channels? Fluids Barriers CNS 15, 17 (2018). source

In the paper

“although individuals with AD still show cycling clock gene expression in multiple brain regions, they lose typical phase coherence within and across regions263”

What the sources say

• Not checked yetcites [263] Cermakian, N., Lamont, E. W., Boudreau, P. & Boivin, D. B. Circadian clock gene expression in brain regions of Alzheimer ‘s disease patients and control subjects. J. Biol. Rhythms 26, 160–170 (2011). source

In the paper

“PD, in particular, is strongly associated with rapid eye moment (reM) sleep behaviour disorder (RBD), as well as excessive daytime sleepiness, insomnia and restless legs syndrome270–273.”

What the sources say

• Not checked yetcites [270] Barone, P. et al. The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov. Disord. 24, 1641–1649 (2009). source
• Not checked yetcites [271] Chaudhuri, K. R. et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson’s disease: the NMSQuest study. Mov. Disord. 21, 916–923 (2006). source
• Not checked yetcites [272] Goodman, A. O., Morton, A. J. & Barker, R. A. Identifying sleep disturbances in Huntington’s disease using a simple disease-focused questionnaire. PLOS Curr. 2, RRN1189 (2010). source
• Not checked yetcites [273] Aziz, N. A., Anguelova, G. V., Marinus, J., Lammers, G. J. & Roos, R. A. Sleep and circadian rhythm alterations correlate with depression and cognitive impairment in Huntington’s disease. Parkinsonism Relat. Disord. 16, 345–350 (2010). source

In the paper

“MitoPark transgenic mice also show a profound disruption of locomotor rhythms in constant conditions and are more vulnerable to changes in the light–dark cycle279.”

What the sources say

• Not checked yetcites [279] Fifel, K. & Cooper, H. M. Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson’s disease. Neurobiol. Dis. 71, 359–369 (2014). source

In the paper

“Treating Bmal1−/− mice with the antioxidant N-acetyl-l-cysteine partially rescues their lifespan and prevents age-dependent pathology292.”

What the sources say

• Not checked yetcites [292] Kondratov, R. V., Vykhovanets, O., Kondratova, A. A. & Antoch, M. P. Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1, 979–987 (2009). source

In the paper

“AD brains show marked loss of neurons in the SCN243,244,262, and SCN neuronal loss correlates with reductions in the amplitude of motor activity rhythms in the same individuals before death240.”

What the sources say

• Not checked yetcites [243] Swaab, D. F., Fliers, E. & Partiman, T. S. The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res. 342, 37–44 (1985). source
• Not checked yetcites [244] Zhou, J. N., Hofman, M. A. & Swaab, D. F. VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol. Aging 16, 571–576 (1995). source
• Not checked yetcites [262] Stopa, E. G. et al. Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J. Neuropathol. Exp. Neurol. 58, 29–39 (1999). source
• Not checked yetcites [240] Wang, J. L. et al. Suprachiasmatic neuron numbers and rest–activity circadian rhythms in older humans. Ann. Neurol. 78, 317–322 (2015). source

In the paper

“Clinical and preclinical data suggest that a lack of appropriate light–dark cues, disturbances in sleep (particularly, reductions in reM sleep) and a deterioration of the SCN pacemaker and its outputs all contribute to sundowning syndrome281.”

What the sources say

• Not checked yetcites [281] Bedrosian, T. A. & Nelson, R. J. Sundowning syndrome in aging and dementia: research in mouse models. Exp. Neurol. 243, 67–73 (2013). source

In the paper

“Time-restricted feeding is also now being used to help treat and/or prevent obesity, as well as metabolic, cardiac and liver disorders327,328.”

What the sources say

• Not checked yetcites [327] Melkani, G. C. & Panda, S. Time-restricted feeding for prevention and treatment of cardiometabolic disorders. J. Physiol. 595, 3691–3700 (2017). source
• Not checked yetcites [328] Mindikoglu, A. L., Opekun, A. R., Gagan, S. K. & Devaraj, S. Impact of time-restricted feeding and dawn-to-sunset fasting on circadian rhythm, obesity, metabolic syndrome, and nonalcoholic fatty liver disease. Gastroenterol. Res. Pract. 2017, 3932491 (2017). source