Sleep, purpose is to remove beta amyloids and metabolites from fluid in interstitial space in brain (similar to lymphatic, but termed glymphatic) Imbalance in proper clearance or wake/sleep cycle or Orexin (wakefulness hormone) leads to Alzheimer

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Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease

Published Online: February 11, 2016

Open Access

DOI: http://dx.doi.org/10.1016/j.smrv.2016.02.002

Article Info

Figures

Fig. 1

Temporal association between homeostatic sleep pressure and CSF concentrations of amyloid beta. The propensity to sleep is considered to be regulated by two interacting mechanisms: a circadian process (C) and a homeostatic process (S) [110] . Process C drives arousal and helps time the onset of normal sleep (driven by e.g., environmental light changes and meal patterns), whereas Process S drives sleep pressure and increases as wakefulness continues and decreases during slow-wave sleep (SWS), a sleep stage that predominates during the first 1/3 of the night. In humans, in a study where samples were collected via an indwelling lumbar catheter, both CSF Aβ40 and Aβ42 fluctuated by 25% with a diurnal pattern (labeled as Aβ in the figure) (higher during wakefulness and lower during sleep), with the lowest Aβ42 levels at around 10:00 h [2] . This corresponds to approximately 04:00 h in sleep time as there is a 6-h lag for brain Aβ to reach the lumbar space [12,57] . Abbreviations: Aβ, amyloid beta; Aβ40, amyloid beta peptide 1–40; Aβ42, amyloid beta peptide 1–42 CSF: cerebrospinal fluid.

Fig. 2

Overview of proposed mechanisms through which disruptions to the sleep-wake cycle form a positive feedback loop with AD pathogenesis in humans. Abbreviations: Aβ, amyloid beta; AD, Alzheimer disease; CNS, central nervous system; BBB, blood–brain barrier; EE, energy expenditure; NFTs, neurofibrillary tangles.

Fig. 3

Scheme illustrating the glymphatic system (primarily based on [37] ). Akin to other cells in the body, brain cells are surrounded by interstitial fluid (ISF), which contains nutrients, proteins and other solutes essential for brain cell survival, but also includes extracellular waste molecules that may be neurotoxic if not cleared properly (e.g., amyloid beta, Aβ). By utilizing real-time assessments of tetramethylammonium diffusion and two-photon imaging in mice, a brain-specific system with a similar function as lymph vessels, for removing ISF from the brain, was discovered in 2012 [62] , and termed the “glymphatic” system as it depends on glial cell functioning. This system promotes clearance of soluble metabolites from the brain [37,62,68,111] . Following entry of CSF through the para-arterial space that surrounds penetrating arteries in the brain, CSF exchanges with parenchymal ISF, moving across the parenchyma. ISF and interstitial solutes are then cleared via exit into the para-venous space surrounding large-caliber cerebral veins [62] . This system was found to depend on the function of astroglial cells that express the protein aquaporin-4 (AQP4; a water channel), in a highly polarized manner along the cells' perivascular endfeet, thus ensheathing the cerebral vasculature. When AQP4 was deleted, CSF influx decreased, coupled with a 70% reduction in ISF solute clearance. This suggests that the system is involved in clearance of substances such as Aβ, the clearance of which was also markedly reduced following deletion of AQP4 [62] . Abbreviations: Aβ, amyloid beta; AD, Alzheimer disease; AQP4, aquaporin-4; CSF, cerebrospinal fluid; ISF, interstitial fluid.

Summary

During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood–brain barrier function – conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease

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Mini Review Open Access
Adolescence and Sleep
Luiz Antonio Del Ciampo1* and Leda Regina Lopes Del Ciampo2
1Department of Puericulture and Pediatrics, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil

2Department of Medicina, Federal University of São Carlos, Brazil

*Corresponding Author:
Luiz Antonio Del Ciampo
PH.D., Professor, Doctor, Department of Puericulture and Pediatrics
Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil
Tel: 55 16 36022479
E-mail: delc...@fmrp.usp.br
Received date: July 04, 2016; Accepted date: July 13, 2016; Published date: July 20, 2016

Citation: Ciampo LAD, Ciampo LRLD (2016) Adolescence and Sleep. J Comm Pub Health Nurs 2:131. doi:10.4172/2471-9846.1000131

Copyright: © 2016 Ciampo LAD, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Community & Public Health Nursing

Abstract
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Keywords

Sleep; Adolescent

Introduction

Sleep is an important physiological condition characterized by a reversible behavioral state with changes in consciousness level and in the responsiveness to internal and external stimuli. It is an active process that involves complex mechanisms in various regions of the central nervous system and is related to various development and maturation processes in the first years of life, such as homeostatic functions for energy conservation, neurotransmitter replacement, synapse and receptor remodeling, modulation of receptor sensitivity, and memory consolidation [1].

Sleeping is a basic physiological need for the body to rest and restore its energy. Sleeping improves memory recall and helps regulate the metabolism in the body and reduces mental fatigue [2]. During sleeping the brain resets itself, removes toxic products accumulated throughout the day, and repairs brain cell damage caused by free radicals [3-5].

Human beings spend about a third of your life sleeping and, although there is no unanimity about the potential functions of sleep, there are three theories that permit a better understanding of the role of this physiological state for the organism. The so-called Restorative Theory proposes that various metabolic processes occur during sleep which serves to prepare the brain and the body for the next period. The Adaptative Theory proposes that sleep can increase animal survival due to immobilization during the periods of greatest danger of the day, reducing the possibilities of their falling prey to other animals. Finally, the Energy Conservation Theory argues that sleep provides a period during which the metabolism is reduced in order to save energy [6,7].

Sleep plays a fundamental role in the somatic, psychological and cognitive domains related to electrophysiological, neurochemical and anatomo-functional changes in the brain. To this end, it is controlled by homeostatic and chronobiological mechanisms. While the former determines its necessity, a circadian rhythm regulates its frequency, with the wake-sleep cycle being determined by the circadian clock [8].

The biological rhythm is important for maintaining a chronogram of hours for sleeping, studying, working, engaging in leisure activities and taking meals. Sleep is an important factor of synchronization between internal variations and environmental cycles. In humans, the best example of this synchronization is the sleep/wake cycle. According to their nature and social organization, human beings are active during the day and their physical functions are mainly oriented towards daytime activities and are related to the biological rhythm [9].

In view of the intense relation existing between the quality of sleep and wakefulness, one of the most immediate results of sleep of poor quality is low performance on the subsequent day, provoking damage during wakefulness such as somnolence, mood swings, anxiety, low self-esteem, slow reasoning, loss of memory, poor school and personal performance, and predisposition to accidents [10,11].

Physiology of the sleep-wake cycle

The sleep-wake cycle is a circadian rhythm which, under natural conditions, oscillates along a period of 24 h. Alternance of light and dark periods, school hours, work shifts, leisure and family activities are some of the exogenous factors that synchronize this cycle. In addition to this synchronization regulated by the environment, the sleep-wake cycle is also regulated endogenously by a neural structure located in the hypothalamus–the suprachiasmatic nucleus–considered to be the circadian biological clock for mammals. Reasons that prevent an individual from sleeping at his habitual time considerably affect the psychosomatic equilibrium, and the adverse effects of the interruption of the circadian rhythm such as night work, for example, have negative repercussions on the wakefulness period [12].

Many metabolic processes necessary for the good functioning of the organism occur during sleep. The beginning of sleep is considered to be related to the activity of endogenous metabolic factors produced during the wakefulness period. During this period, the metabolites accumulate in the brain as a consequence of the increased neuronal activity on the structures that promote wakefulness and of the overall increase of neuronal activity [1]. The slow accumulation of these metabolic factors increases the inertia of sleep and, when their level becomes critically high the brain responds by reducing the neuronal activities in the regions that promote wakefulness. The reduction of the neuronal activity determines the end of wakefulness and initiates the passive process of sleep. In turn, during sleep the metabolites reach a critically low level which causes disinhibition of neuronal activity in the brain regions that promote wakefulness, increasing the activity in the brain regions that promote behavioral states of wakefulness [13]. Over the last few years, some metabolic factors that initiate sleep have been identified, such as adenosine, the neuroinhibitory amino acids GABA and glycine, prostaglandin D2, cytokines, the alpha melanocyte stimulating hormone, somatostatin, and tumor necrosis factor alpha [14-16].

Two behavioral states are identified during sleep: synchronized or non-rapid eye movement (NREM) and desynchronized, paradoxical or rapid eye movement (REM). NREM sleep is characterized by synchronous cerebral electrical activity with its own elements and is divided into stages I, II and III which represent the progressive depth of sleep. During NREM sleep there is also a reduction of the activity of the autonomous sympathetic nervous system and an increase of parasympathetic tonus to higher levels than during wakefulness. Respiratory and heart rates, cardiac output, arterial pressure, pupil diameter, intestinal movements and galvanic skin resistance do not undergo abrupt changes. REM sleep, in turn, is characterized by the so-called electroencephalographic desynchronization, which manifests when rapid eye movements occur, as well as by brief muscle contractions of the limbs and muscular atonia, causing skeletal muscle to become paralyzed. There is instability of the autonomic sympathetic nervous system, with variations in heart and respiratory rates, cardiac output, arterial pressure, coronary and cerebral blood flow, pupil size and penile erection. In contrast, the tonus of the parasympathetic system is essentially the same in NREM sleep [17-19].

Under normal conditions, the sleep stages occur in a cyclic manner during the night (ultradian cycle), starting with the succession of one to three NREM stages [20,21].

Melatonin synchronizes the sleep-wake rhythm and various biological rhythms such as body temperature, corticotropin releasing hormone and adrenocorticotropic hormone in addition to cortisol, which show cyclic changes during the 24 h. Thus, when sleep habits become disorganized, changes in the production of these hormone may occur, with the respective clinical manifestations associated with them [10,22,23].

Two biological mechanisms acting on sleep regulation are recognized in association with environmental factors. One is called circadian (C process) and the other homeostatic (S process). The homeostatic process is related to the increase in the tendency to sleep during the day and is subjected to the effects of lack of sleep. On the other hand, the circadian process is responsible for the predisposition to sleep during the dark phase of the day. In adolescence there is less inhibition of the secretion of melatonin at the beginning of the light phase of the day and a slower accumulation of the tendency to sleep during the day, which may lead to a phase delay, more commonly observed in more advanced pubertal periods [24]. Thus, the biological and behavioral changes that occur during adolescence lead to a phase delay that, according to the social and school context, will reflect on a reduction of hours of sleep and an increase in daytime somnolence [25,26].

Stress is a factor that strongly influences sleep because it involves an increased secretion of circulating cortisol which may lead to suppression of REM sleep, an increase of superficial sleep, and difficulty in falling asleep and staying asleep. Considering the current life conditions associated with a large amount of appointments and tasks to be performed, adolescents are subjected to one of the main effects of stress, i.e., the reduction of sleep quality and quantity [27].

Lack of sleep provokes a reduction of metabolism in frontal brain regions (responsible for the planning and execution of tasks) and in the cerebellum (the center of motor coordination), leading to difficulties in accumulating knowledge, to mood changes, and to impairment of creativity, attention, memory and equilibrium [28].

Adolescents and Sleep

Adolescence is characterized as a phase of life during which important biopsychosocial, cognitive and behavioral changes occur, leading to repercussions on various homeostatic mechanisms, also regarding the pattern of the sleep-wake cycle. Among the various structural modifications that occur in the body, recent discoveries have pointed out that, at the beginning of puberty, the volume of gray mass existing in the frontal and parietal lobes reaches a peak, followed by a later decrease, and that this tissue is sensitive to the variations suffered by the organism, as observed for those related to sleep [29].

Sleep plays an important role in the physical and emotional development of adolescents, who are going through a period of intense learning and differentiations. Adolescent is a being biologically programmed to sleep and wake up later, with his brain not being in a wakefulness state for most of the morning. Paradoxically, however, nowadays various elements contribute to preventing the adolescent from sleeping adequately in view of the social pressures that diversify and increase his activities such as excessive use of electronic devices, new affective relationships, parties, etc. All of these factors cause a reduction of nighttime sleep, with consequent somnolence during the day [11,12,30]. Prolonged exposure to electronic devices can result in nocturnal melatonin suppression or a delay of melatonin release through increased nocturnal stimulation of the circadian system [31].

Social activities and habits in general have migrated to increasingly more nocturnal times, while classes start in the morning, leading to an important reduction of sleep hours and a persistent sleep debit throughout the week [32,33]. In turn, the technological era has caused marked transformations in today’s life due to the introduction of television and, more recently, of microcomputers in the home. With the growth of the internet, the habit of surfing on the web for long periods of time is becoming increasingly more intense, especially among adolescents, who practically “surf ” throughout the night at the expense of regular hours of sleep for a good physical and psychological development. One of the great current challenges for adolescents is to try to keep a regular sleep-wake cycle, to fulfill social demands and to satisfy their sleep necessities [34,35].

Two major health problems can be associated with sleep deprivation. Sleep deprivation and epilepsy have a complex bidirectional relationship because lack of sleep can increase the likehood of seizure recurrence due the activating interictal activity and recurrent oxygen desaturation [36-38]. Chronic headache has also been associated with short sleep duration with increased frequency and severity acting as headache triggers [39-41].

Nowadays the main characteristics of the sleep-wake cycle of adolescents are to go to bed later, to get up early, and to present irregular and variable sleep patterns between week days and weekends, insufficient periods of sleep, and daytime somnolence. As a consequence, adolescents are quite vulnerable to sleep disorders, especially insomnia [42,43]. The estimate is that 14% to 33% of all adolescents complain about sleep problems and that 10% to 40% of middle school students have moderate or transitory sleep deprivation or insufficiency in addition to difficulties in school performance and behavior and mood disorders during the daytime [44].

The duration of nighttime sleep plays an important role in the health of adolescents, who are going through a period of intense learning and differentiation, has a significant impact on their physical and psychological well-being and, when reduced, is associated with behavioral and neurocognitive problems, especially disorders of learning and attention deficit, lower academic performance, mood swings and reduced opportunities for socialization and for the search of professional activities [34,35]. Studies have suggested that adolescents need 9 to 9 ½ h of sleep per night and when they do not satisfy this need may have more daytime somnolence, attention and concentration difficulties, low school performance, as well mood swings, behavioral problems, depression, predisposition to accidents, delayed pubertal development, greater weight gain and greater use of alcohol and of psychostimulant drugs [11,35,36].

In addition to the impact of these biological and environmental factors, social demands such as home tasks, extracurricular activities and work after school hours can significantly affect the sleep patterns of adolescents. A wide variability in the sleep-wake pattern is observed during the weeks, associated with the habit of going to sleep later during the weekend, as if to compensate for the accumulated sleep debt. This phenomenon, called oversleeping, contributes to a rupture of circadian rhythm and to a reduction of daytime wakefulness [45].

The increase of weight and height proportions is one of the main phenomena that occur during adolescence and is directly related to the action of growth hormone (GH), whose secretion is affected by various external stimuli, among them sleep. In adolescence, GH secretion mainly occurs during the hours of deep sleep, with 80% of its concentration being released in one or two pulses during stage III sleep each night [46]. Fewer hours and a poor quality of sleep may interfere with GH secretion, leading to delayed sexual maturation [47].

Adolescents show a delay during puberty, reaching maximum vespertine behavior close to 20 years of age, with girls reaching this peak before boys, a fact that can also be considered a marker of the end of adolescence [48].

The hours of sleep during adolescence have decreased with passing years. Dollman et al. [49] compared the duration of sleep in a sample of young Australians aged 10 to 15 years between 1985 and 2004 and observed a reduction of hours of sleep in the second evaluationc compared to the first. In addition, boys went to sleep later than girls in 2004, differences that were not observed in the first evaluation. Among adolescents, night attractions such as television, games and the internet cause a delay in bedtime during week days and weekends, and a later wake up time during the weekend. On week days, school schedules require early awakening, reducing the time in bed and sleep hours; however, the need for sleep does not decrease during adolescence [50]. A survey conducted on American adolescents showed that more than 60% reported that they slept less than seven hour per night during the week, i.e., much less than the 8 ½ to 9 ½ h recommended [51].

Conclusion

For a human being living in harmony with himself and with his environment it is necessary to observe a daily period of sleep. The physical and emotional events that occur during the second decade of life, associated with the stress of social demands, cause the adolescent to be an individual with difficulties in organizing his daily schedule, including the periods of sleep.

On this basis, it is important to be aware of the specific characteristics of the sleep-wake cycle and of the events that occur during adolescence so that it will be possible to offer guidelines about how to sleep well and to enjoy the benefits provided by sleep to the organism. In addition, when necessary, this life history should permit a complete understanding of the educational, social and professional activities.

It should be remembered that adolescents live in a challenging, dynamic and stimulating world that offers constant information competing with the guidelines that the hebiatrist may provide. At this time, it is fundamental for the professionals to establish an optimal relationship with their patients, with the prevalence of a frank and responsible dialogue.

Working with adolescents so that they will understand concepts such as “lost hours of sleep are not recovered” and that sleep periods programmed later will not compensate for a night of poor sleep is the key to the initiation of good sleep hygiene. In addition, adolescents should be advised that adequate practice of regular physical activity for more than 60 minutes, the reduction of idle time in front the computer and the television and a minimal routine for the night period can greatly contribute to a satisfactory period of sleep.

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Though this article states melanocytes stimulating hormone is related to sleep (I assume induction they infer) but it gives no info. And nothing has ever come out of web ......that is a directl relation to just sleep. Indirectly indications so far and new discovery is that msh is affecting glial cells and the nigra and immune cells in the brain as well as there must be a affect on glutamate and energy metabolism in the brain if it is systemic.

And if effects on energy are there this may substantiate the studies indicating the "clean out" of waste.

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https://www.huffingtonpost.com/entry/scientists-somehow-just-discovered-a-new-system-of_us_59e50315e4b0a741e4b3531a

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Volume 560 Issue 7717, 9 August 2018
Volume 560 Issue 7717
Brain drain
The task of removing waste products such as cellular debris and toxic molecules from the body’s tissues is performed by lymphatic vessels. In this week’s issue, Jonathan Kipnis and his colleagues reveal that the brain also makes use of this system, by moving macromolecular waste in cerebral fluids to be drained through lymphatic vessels located within the meninges — the membranes that cover the brain. They find that, in normal mice, cognitive function is reduced if the meningeal lymphatics become impaired. The researchers also show that ageing damages the lymphatics and that restoring their function is associated with recovered ‘brain cleansing’ and improved memory. Working with a mouse model for Alzheimer’s disease, the team reveals that if the meningeal lymphatic vessels are disrupted, clearance of the protein amyloid-β is impaired leading to accumulation in the brain, which worsens the amyloid pathology. The team suggests that targeting decline in the meningeal lymphatic system could be a useful therapeutic route to help combat age-related cognitive dysfunction. show less

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Published: May 26, 2022 11.07pm EDT

Author

David Wright
Associate Professor of Medical Imaging, Monash University

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David Wright receives funding from the NHMRC and FightMND. He has previously received funding from the Bethlehem Griffiths Research Foundation to investigate glymphatic function in ALS.

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Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is the most common form of motor neuron disease. People with ALS progressively lose the ability to initiate and control muscle movements, including the ability to speak, swallow and breathe.

There is no known cure. But recently, we studied mice and identified a new target in the fight against this devastating disease: the brain’s waste clearance system.

Neurodegenerative diseases – including Parkinson’s disease, Alzheimer’s and multiple sclerosis – share many similarities, even though their clinical symptoms and disease progression may look very different. The incidence of these diseases increase with age. They are progressive and relentless, and result in gradual loss of brain tissue. We also see waste proteins accumulate in the brain.

Our new research looked at how the glymphatic system, which removes waste from the brain, could prevent ALS.

Protein chains, folds and misfolds

Inside our bodies, long protein chains fold to form functional shapes that allow them to perform specific tasks like creating antibodies to fight off infection, supporting cells or transporting molecules.

Sometimes this process goes awry, resulting in “misfolded” proteins that clump together to form aggregates. Misfolded protein can grow and fragment, creating seeds that spread throughout the brain to form new clusters.

The accumulation of waste proteins begins early in the neurodegenerative disease process – well before the onset of symptoms and brain loss. As researchers, we wanted to see if eliminating or slowing the spread of these waste proteins and their seeds could halt or slow the progression of disease.

Targeting waste removal

The glymphatic system removes waste, including toxic proteins, from the brain.

This brain-wide network of fluid-filled spaces, known as Virchow-Robin spaces, is mostly switched off while we’re awake. But it kicks into gear during sleep to distribute compounds essential to brain function and to get rid of toxic waste.

This may explain why all creatures, great and small (even flies), need sleep to survive. (Interestingly, whales and dolphins alternate their sleep between brain hemispheres, keeping the other hemisphere awake to watch for predators and alerting them to breathe!)

Unlike us, dolphins sleep with one side of their brain at a time. Unsplash/NOAA, CC BY

As we age, sleep quality declines and the risk of neurodegenerative disease, including ALS, increases.

Sleep disturbances are also a common symptom of ALS and research has shown a single night without sleep can result in increased accumulation of toxic waste protein in the brain. As such, we thought glymphatic function might be impaired in ALS.

Ageing mice

To investigate this, we looked to mice. The animals were genetically modified to express human TDP-43 – the protein implicated in ALS. By feeding these mice food containing an antibiotic (doxycycline), we were able to turn the TDP-43 protein expression off and they aged normally. But when the mice are switched to normal food, TDP-43 expression is turned on and misfolded proteins begin to accumulate.

Over time, the mice display the classical signs of ALS including progressive muscle impairments and brain atrophy.

Using magnetic resonance imaging (MRI) to see brain structure, we investigated glymphatic function in these mice just three weeks after turning on TDP-43 expression.

As we watched the glymphatic system go to work, we saw the TDP-43 mice had worse glymphatic clearance than the control mice that had not been genetically modified. Importantly, these differences were seen very early in the disease process.

Our study provides the first evidence the glymphatic system might be a potential therapeutic target in the treatment of ALS.

How can we improve glymphatic function?

Not all sleep is equal. Sleep includes both rapid eye movement (REM) and non-REM sleep. This latter stage includes slow wave sleep – when the glymphatic system is most active. Sleep therapies that enhance this phase may prove to be particularly beneficial for preventing diseases like ALS.

Sleep position is also thought to affect glymphatic clearance.

Research conducted in rodents has demonstrated glymphatic clearance is most efficient in the lateral (or side-sleeping) position, compared to either supine (on the back) or prone (front-lying) positions. The reasons for this are not yet fully understood but possibly relates to the effects of gravity, compression and stretching of tissue.

Lifestyle choices may be helpful in improving glymphatic function too. Omega-3, found in marine-based fish, has long been considered to be beneficial to health and reduced risk of neurodegenerative diseases. New research shows these benefits may be partly due to the positive effect of Omega-3 on glymphatic function.

Moderate consumption of alcohol has been shown to improve waste clearance. In mouse studies, both short and long-term exposure to small amounts of alcohol were shown to boost glymphatic function while high doses had the opposite effect.

Exercise has also been shown to be beneficial.

All these studies show small lifestyle changes can improve brain waste clearance to minimise the risk of neurodegenerative disease. Next, research needs to focus on therapies directly targeting the glymphatic system to help those already suffering from these debilitating diseases.

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The Effects of Light and the Circadian System on Rhythmic Brain Function

Charlotte von Gall

Institute of Anatomy II, Medical Faculty, Heinrich Heine University, 40225 Dusseldorf, Germany

Academic Editor: Etienne Challet

Int. J. Mol. Sci. 2022, 23(5), 2778; https://doi.org/10.3390/ijms23052778

Received: 4 February 2022 / Revised: 22 February 2022 / Accepted: 1 March 2022 / Published: 3 March 2022

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Synchronization within the Mammalian Circadian System)

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Abstract

Life on earth has evolved under the influence of regularly recurring changes in the environment, such as the 24 h light/dark cycle. Consequently, organisms have developed endogenous clocks, generating 24 h (circadian) rhythms that serve to anticipate these rhythmic changes. In addition to these circadian rhythms, which persist in constant conditions and can be entrained to environmental rhythms, light drives rhythmic behavior and brain function, especially in nocturnal laboratory rodents. In recent decades, research has made great advances in the elucidation of the molecular circadian clockwork and circadian light perception. This review summarizes the role of light and the circadian clock in rhythmic brain function, with a focus on the complex interaction between the different components of the mammalian circadian system. Furthermore, chronodisruption as a consequence of light at night, genetic manipulation, and neurodegenerative diseases is briefly discussed.

Keywords: suprachiasmatic nucleus; entrainment; masking; chronodisruption; molecular clockwork; behavior; cognition; hippocampus; light at night; phase shift; melatonin; glucocorticoids; circadian rhythms; circadian clock; clock genes

1. Introduction

Life on earth has evolved under the influence of rhythmic changes in the environment, such as the 24 h light/dark cycle. Living organisms have developed internal circadian clocks, which allow them to anticipate these rhythmic changes and adapt their behavior and physiology accordingly. This is most obvious for plants in which the anticipation of the time window for photosynthesis, the light phase, provides a selection advantage over plants that simply react to the onset of the light phase. Moreover, for the early cold-blooded terrestrial animals, anticipating the light phase and, thus, the time with higher ambient temperature and better availability of visual cues has been a selection advantage. In contrast, for the early (warm-blooded) mammals, which developed in the Mesozoic (about 250 million years ago), anticipating the twilight and the dark phase, thus the time window for avoiding the diurnal predatory dinosaurs was crucial. Presumably, the early mammals gradually extended their behavior from the nocturnal towards the twilight phases of the day, resulting in activation of both cone- and rod-based vision [1].

Consequently, the neocortex, a brain region characteristic for mammals, which is responsible for higher-order brain functions, such as sensory perception, cognition, as well as the planning, control, and execution of voluntary movement, initially developed in nocturnal/crepuscular species. Only in the Cenozoic, when many species, including the non-avian dinosaurs, became extinct, mammals were released from this predatory pressure and diurnality developed among mammals [2]. Primates are among the earliest mammals to exhibit strict diurnal activity, approximately 52–33 million years ago [2]. Hence, mammals are by default nocturnal, and diurnalty as in humans is a relatively new invention and more or less an exception among the mammalian species. However, the visual system in primates is highly flexible and can function under bright and dim light conditions, hence allows evolutionary switching of lineages from one activity pattern to the other, according to the selective pressure [3]. About 40% of all mammal species are rodents. Among them there are very few diurnal species, such as Arvicanthis, Psammomys, and Ictidomys (formerly Spermophilus) [4]. Importantly, most rodents, including Mus musculus and Rattus norwegicus, the most commonly used mammals in the laboratory, are nocturnal. However, the aspect of different temporal niches is often not sufficiently taken into consideration when translating basic research in rodents into human applications. The aim of this broad review article is to highlight the role of light on rhythms in physiology and behavior, especially in nocturnal rodents from a neuroanatomical point of view, and to emphasize the important distinction between light-driven/time-of-day-dependent and endogenously driven/circadian rhythms.

2. The Role of Light and the Circadian Clock for Rhythmic Brain Function2.1. The Mammalian Circadian System

In mammals, the circadian clock is hierarchically organized in a circadian system. The central circadian rhythm generator is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Rhythmic output of the SCN governs subsidiary circadian oscillators in the brain and the periphery. The SCN and the subsidiary oscillators consist of more or less strongly coupled cellular oscillators, each comprising a molecular clockwork composed of transcriptional/translational feedback loops of clock genes (reviewed in [5]). The SCN controls subsidiary circadian oscillators in the brain primarily via neuronal connections while peripheral oscillators are regulated via the rhythmic function of the autonomous nervous system [6] and the endocrine system [7].

The hormone of darkness, melatonin, and the stress hormone glucocorticoid [8] (see below) are important rhythmic signals for subsidiary circadian oscillators in the brain and in the periphery. The light input into the circadian system is provided by a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs). There is increasing evidence that rhythmic light information is not only provided to the SCN but also directly or indirectly to many other brain regions, thus driving time-of day-dependent rhythmic brain function (Figure 1).

Figure 1. The mammalian circadian system is highly complex and hierarchically organized. Almost all brain regions and organs comprise a molecular clockwork (clocks) which controls rhythmic cell function. Rhythmic light information is provided directly and indirectly to many brain regions (green arrows) and drives time-of-day-dependent rhythms in brain and periphery. The central circadian rhythm generator which is located in the suprachiasmatic nucleus (SCN) of the hypothalamus is entrained by light. SCN lesion results in loss of circadian rhythms. Rhythmic output of the SCN governs subsidiary circadian oscillators in the brain (red arrows).

Different nuclei in the hypothalamus (hyp) control rhythmic physiology and behavior via neuronal connections including the autonomous nervous system (blue solid arrows) and endocrine signals (blue dashed arrows) via the pituitary (pit). Rhythmic endocrine signal from the pineal gland and the periphery (blue dashed lines) provide additional rhythmic signals for the brain. The liver is depicted exemplarily for the gastrointestinal system. Monoamines and catecholamines from the brain stem provide important rhythmic drive for alertness and motivation at the level of the forebrain. Based on [9,10,11].

2.2. Light Input into the Circadian System—Entrainment and Masking

Two main mechanisms help to specialize in a nocturnal or a diurnal niche [12]. In the mechanism called entrainment, light serves as a signal for the SCN, to match the period and the phase to the environmental oscillator, the light/dark regime. Adjusting the period is necessary, as the endogenous rhythm, persisting in constant darkness, is close to but not exact 24 h. The SCN in turn helps to anticipate the rhythmic changes in the environment and controls activity during the dark or the light phase. This is important, as many nocturnal mammals live in dark burrows and experience the environmental light conditions only when leaving the safe surrounding of the nest. Entrainment is adaptive, as the lengths of the light and dark phase change according to the seasons, depending on the latitude. In the mechanism called masking, light directly affects behavior obscuring the control from the circadian clock [13]. Masking is especially prominent in nocturnal species, and, here, light can have two opposite effects on activity depending on irradiance levels. In dim light, activity is increased compared to complete darkness. This enhancing effect of dim light, which is presumably due to increased confidence based on visual input [14], is called positive masking [12]. However, in complete darkness, activity is higher, despite the absence of visual cues, than under standard (bright) light conditions. This suppressive effect of bright light on activity is called negative masking [12]. Similarly, nocturnal animals prefer dark or dimly illuminated areas over brightly illuminated areas. This light aversion is strong enough to counteract the natural tendency to explore a novel environment, as shown by the light–dark test [15], a paradigm extensively used for tests on classic anxiolytics (benzodiazepines) [15], as well as anxiolytic-like compounds, such as serotonergic drugs or drugs acting on neuropeptide receptors (reviewed in [16]). In both diurnal and nocturnal mammals, light at night also elicits acute effects on physiological parameters, such as core body temperature and heart rate, as well as hormone secretion (see below). Importantly, the detection of visual information in the mammalian retina is conveyed by two parallel pathways, the rod–cone system for image-forming-vision and the melanopsin-based system of the ipRGCs for non-image-forming irradiance detection. Although ipRGCs are essential for the adaptive physiological responses to light, such as the pupillary light reflex [17], as well as circadian entrainment [18,19], and contribute to scotopic vision [20], both the rod–cone system and the ipRGCs seem to contribute to masking and light aversion [21]. Importantly, many commonly used laboratory mouse strains carry mutations that affect visual and/or non-visual physiology (reviewed in [22]).

Under natural conditions, entrainment and masking work in a complementary fashion [23]. However, in the laboratory, the two mechanisms can be segregated. As mentioned above, entrainment is highly adaptive to different photoperiods. In most animal facilities, the standard photoperiod is 12 h light and 12 h dark (LD 12:12), although some animal facilities have opted for different light conditions (e.g., LD 16:8), as the photoperiod has a high impact on reproduction in some species. The circadian clock also rapidly entrains to a phase shift one experiences when travelling across time zones or if the LD cycle is inverted. The re-entrainment capacity after jet lag is dependent on intrinsic factors, such as the robustness of the circadian clock or the signaling of hormones, such as melatonin [24]. Furthermore, the speed of re-entrainment to a phase shift depends on the direction; entrainment is usually faster in response to a phase delay than a phase advance [25]. Interestingly, this is the same in the diurnal human [26]. However, in nocturnal animals, brief light pulses during the early and late night are strong resetting cues for phase delays and advances of the circadian clock, respectively [27]. At the cellular level, photic resetting of the SCN molecular clockwork involves activation of the p44/42 mitogen-activated protein kinase (MAPK) signaling cascade, phosphorylation/activation of the transcription factor cAMP-response-element-binding protein (CREB) [28], the induction of the marker of neuronal activity c-Fos [29], inhibitors of DNA binding proteins [30], and expression of the clock gene Per1 [31]. In order to study entrainment in the absence of the interfering masking effects of light, nocturnal animals can be housed under a so-called skeleton photoperiod, consisting of two discrete pulses of light during the early (dawn) and the late (dusk) light phase [32]. For entrainment to this lighting schedule, the intergeniculate leaflet is essential, which receives direct photic information from the ipRGCs [33].

2.3. The Brain Molecular Clockwork

Various brain functions, such as sleep, wake, foraging, food intake, alertness, emotion, motivation, and cognitive performance, controlled by different brain regions, show circadian rhythms. Moreover, any information is processed in a temporal context. Consistently, many brain regions harbour circadian oscillators, which are governed by the SCN [34]. At the cellular level, these oscillators are composed of single cells each harbouring a molecular clockwork composed of transcriptional/translational feedback loops of clock genes. The clock genes encode for activators of transcription, such as CLOCK and its forebrain-specific analog NPAS2 [35], BMAL1, and ROR, as well as the repressors of transcription PER1 and PER2, CRY1, CRY2, and REV-ERBα [5].

The molecular clockwork drives the rhythmic expression of clock controlled gene (see below) and posttranscriptional processes (reviewed in [36]) and modulates the chromatin landscape [37], thus regulating rhythmic cell function at multiple levels. The molecular clockwork in the SCN and subordinate extra-SCN brain circadian oscillators drives various rhythms in neuron and glia function including ATP concentration [38], neuronal electrical activity (reviewed in [39]), metabolism [40], redox homeostasis (reviewed in [41]), tyrosine hydroxylase expression in dopaminergic neurons [42], dopamine receptor signalling in the hippocampus [43], and extracellular glutamate homeostasis [44]. In addition, some rhythms in the SCN are time-of day-dependent and do not persist in constant darkness, such as rhythmic expression of connexion 30 [45], which contribute to astrocyte gap junctions and hemichannels (reviewed in [46]), as well as the stability of circadian rhythms and re-entrainment under challenging conditions [45]. Circadian clock gene expression in the SCN and the hippocampus persists with high robustness in vitro, indicating a strong coupling of single cell oscillators, while it damps rapidly in other brain regions, indicating a weak coupling [47,48,49]. Mice with a targeted deletion of the essential clock gene Bmal1 are arrhythmic under constant environmental conditions [50], so a loss of function in a single gene strongly affects circadian rhythmicity. In mouse models for compromised molecular clockwork function, such as Bmal1-deficient mice, Per1/2 double mutants, and Cry1/Cry2 double mutants, circadian rhythms are abolished, while various parameters of physiology and behaviour are rhythmic under the LD 12:12 conditions due to masking [50,51,52]. This emphasizes the strong impact of the environmental light/dark conditions on rhythmic brain function. In this context, it is important to note that Cry1/Cry2 double mutants and Bmal1-deficient mice show deficits in retinal visual physiology [53] and, consequently, impaired visual input into the circadian system [54,55]. Nevertheless, even under LD 12:12 conditions, many brain functions, such as spatial memory consolidation and contextual fear [56,57], adult neurogenesis [58], and sleep architecture [59] are affected in Bmal1-deficient mice, indicating the importance of this clock gene/transcription factor for general brain function.

2.4. Rhythmic Gene and Protein Expression in the Brain

About 43% of all coding genes and about 1000 noncoding RNAs show circadian rhythms in transcription somewhere in the body, largely in an organ/tissue-specific manner [60,61,62]. The rhythmic transcriptome in peripheral organs is dependent on the SCN [62] but continues to oscillate in vitro for a few cycles [63]. Only 22% of circadian rhythmic mRNA is driven by de novo transcription, indicating that the molecular clock drives transcription and posttranslational modification [37]. Moreover, the epigenetic landscape is modulated in a circadian manner [37]. A comparable number of transcripts show a circadian oscillation in the SCN and the liver, while only about 10% of them show an overlap [61]. The core clock genes Arntl (encoding for Bmal1), Dbp, Nr1d1 and Nr1d2 (encoding for Rev-Erb alpha and beta, respectively), Per1, Per2, and Per3, as well as the clock controlled genes Usp2, Tsc22d3, and Tspan4 oscillate in many organs and parts of the brain [60]. Importantly, many commonly used drugs target the products of the circadian genes, so the timed application of these drugs, chronotherapy, might maximize efficacy, and minimize side effects [60]. In accordance with the important role of the brain stem in the regulation of autonomous and vital functions, more than 30% of the drug-target circadian genes listed in the study by Zhang et al. (2014) are rhythmically expressed in this part of the brain. In the retina, about 277 genes show a circadian rhythm, implicated in a variety of functions, including synaptic transmission, photoreceptor signalling, intracellular communication, cytoskeleton reorganization, and chromatin remodelling [64]. Intriguingly, in LD 12:12, about 10 times as many genes oscillate, indicating that the LD cycle drives the rhythmic expression of a large number of genes in the retina [64]. In the forebrain synapses, a comparable amount of genes (2085, thus 67% of synaptic RNAs) show a time-of-day-dependent rhythm, and a high percentage of these genes remain rhythmic in constant darkness (circadian) [65]. Interestingly, the rhythmic genes in the forebrain synapses can be segregated into two temporal domains, predusk and predawn, relating to distinct functions; predusk mRNAs relate to synapse organization, synaptic transmission, cognition, and behaviour, while predawn mRNAs relate to metabolism, translation, and cell proliferation or development [65]. The oscillation of the synaptic proteome resembles those of the transcriptome [65] and a high percentage show an oscillation in the phosphorylation state [66].

Sleep Deprivation, Epilepsy, and Glucocorticoids Affect Gene and Protein Expression in the Brain

Sleep deprivation induced by gentle handling, cage tapping, and the introduction of novel objects during the light/inactive phase affects clock gene expression in the cerebral cortex [67] and leads to a reduction in transcript oscillation in the entire brain to about 20% [68]. This indicates that the sleep disruption itself, and/or the manipulation, as well as the associated additional light exposure, which mice usually do not experience while sleeping, strongly affects rhythmic transcription. On the other hand, it shows that only 20% of the rhythmic transcriptome in the brain is resilient to sleep deprivation, manipulation, and light exposure during the light/inactive phase. In forebrain synapses, sleep deprivation has a higher impact on the proteome and on rhythmic protein phosphorylation than on the transcriptome [65,66]. In this context, it is important to note that traditional sleep deprivation protocols using sensory-motor stimulation induces stress associated with a rise in circulating corticosterone [69], an important temporal signal within the circadian system (see below). Corticosterone strongly contributes to the sleep-deprivation-induced forebrain transcriptome [70]. Among the genes assigned to the corticosterone surge are clock genes, as well as genes implicated in sleep homeostasis, cell metabolism, and protein synthesis, while the transcripts that respond to sleep loss independent of corticosterone relate to neuroprotection [70]. The time-of-day-dependent oscillation in hippocampal transcriptome and proteome is affected by temporal lobe epilepsy [71]. Although epilepsy could be considered a chronic stress model [72], little is known on the contribution of glucocorticoids in these alterations. More research avoiding stress as a confounder is needed to explore the effect of sleep and neurological disorders on rhythmic brain function.

2.5. Circadian and Light-Driven Brain Function2.5.1. Rhythmic Hormone Release

The circadian rhythm of melatonin synthesis in the epithalamic pineal gland is one of the best characterized functions of the mammalian circadian system. The control of rhythmic melatonin synthesis comprises the rhythmic activation of the sympathetic nervous system by GABAergic neurons in the SCN projecting to pre-autonomous nerve cells in the paraventricular nucleus (PVN), and these neurons, in turn, project to preganglionic sympathetic neurons in the intermediolateral column of the spinal cord. The pineal gland is activated by postganglionic fibres from the superior cervical ganglia. Remarkably, in both nocturnal and diurnal species, the release of norepinephrine during the dark phase drives rhythmic melatonin synthesis and release. As rhythmic melatonin synthesis is governed by the circadian clock, it persists in constant darkness and can entrain to the environmental light/dark conditions. The duration of the melatonin signal increases with the length of the night, so melatonin provides a systemic signal not only for the phase of the night but also for anticipation and adaptation to seasonal changes in the photoperiod (reviewed in [10]), which is particularly relevant for seasonal breeders. Light, especially at a lower wavelength (<555 nm), during the dark phase acutely inhibits melatonin synthesis. The melatonin receptors MT1 and MT2, which belong to the superfamily of G-protein-coupled receptors, are widely distributed within the brain, including the SCN, and the periphery. Melatonin provides an important systemic time cue not only during adulthood but also during prenatal and early postnatal development when the components of the circadian system are not yet fully matured. During aging, the decrease in melatonin production and sensitivity is associated with an increasing deterioration of circadian rhythms. Interesting, many mouse strains, including those of the widely used C57BL/6 mice, do not produce melatonin as a result of spontaneous mutations [73], indicating that melatonin signalling is dispensable for living under laboratory conditions. In humans, melatonin has effects on sleep propensity, temperature regulation, and alertness and may modulate pain sensation, immune function, and metabolic function, such as insulin production (reviewed in [10]). Melatonin and melatonin receptor agonists are used for the treatment of jet lag symptoms, the entrainment of circadian rhythms in blind people, and major depression and insomnia, diseases considered to be associated with circadian dysfunction, as mentioned above.

The circadian rhythm in glucocorticoid secretion from the adrenal provides an important systemic signal within the mammalian circadian system. Both the secretion in response to stress and the rhythmic basal secretion are regulated by the hypothalamo-pituitary-adrenal (HPA) axis. This comprises the release of corticotropine releasing hormone (CRH) from parvocellular neuroendocrine neurons in the PVN, which controls the secretion of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary into the systemic circulation and ACTH activates the release of glucocorticoids. The circadian rhythm of glucocorticoid is controlled by a vasopressinergic SCN projection to the PVN. In both diurnal and nocturnal animals, glucocorticoid levels start to rise in the second part of the inactive phase and reach peak values around wake time. Importantly, in nocturnal animals, brief light pulses during the subjective night leads to an increase in glucocorticoid levels comparable to those induced by a strong stressor [74]. Glucocorticoid receptors are widely distributed in the brain (except the SCN) and the body. Glucocorticoids are essential for life and regulate a variety of important cardiovascular, respiratory, metabolic, immunologic, and homeostatic functions. Interestingly, glucocorticoid signalling in utero is presumably a key mediator of prenatal stress and affects neurodevelopment and foetal epigenetic landscape [75]. Glucocorticoids have been shown to control various subsidiary clocks in the periphery, such as the liver, kidney, and heart [8] (reviewed in [76]). In addition, glucocorticoid signalling affects rhythmic gene expression in the brain regions implicated in emotions and cognition, such as the raphe nuclei, the amygdala, and the hippocampus [77,78,79,80].

2.5.2. Rhythms in Food Intake

Although the regulation of food intake/foraging and energy metabolism strongly rely on homeostatic feedback signals, the circadian clock provides temporal organization (reviewed in [81]). It facilitates the temporal occurrence of related functions, such as food intake and glycogenesis, separates conflicting functions and behaviours, such as eating and sleep, and allows for the anticipation of rhythmic changes in the environment, such as the light/dark cycle of limited food availability (reviewed in [81]). An important homeostatic signal is the hormone ghrelin, released from gastric cells under fasting conditions, mediating the release of the neuropeptides neuropeptide Y and Agouti-related peptide from the arcuate nucleus of the hypothalamus. These neuropeptides, in turn, activate the release of orexin from the lateral hypothalamus (LH) and melanin-concentrating hormone. Orexin seems to play a major role in linking feeding behaviour and activity [82] (for the role of orexin in activity, see below). Anorexigenic humoral signals involve insulin and leptin, released from the pancreas and adipose tissue, respectively. Both signals converge on pro-opiomelanocortin expressing Acr neurons, and the α-melanocyte-stimulating hormone mediates hypophagic effects and increases in energy expenditure via the PVN, the dorsomedial hypothalamus (DMH), and the ventromedial hypothalamus (VMH) (reviewed in [81]). The homeostatic regulation of food intake and energy expenditure involves additional modulators, such as endocannabinoids and structures in the brain stem (reviewed in [81]). The SCN plays a major role for circadian rhythms in food intake [83]. In nocturnal animals, restricting the availability of food to the light phase affects many circadian rhythms: the animals show an increase in body temperature and glucocorticoid levels and become active a few hours in advance of the time of limited food availability. This rhythmic food anticipatory activity persists even under food deprivation for a couple of days, indicating an intrinsic time-keeping mechanism (reviewed in [84]). Curiously, this time-keeping mechanism of food anticipatory activity persists even if the SCN is disabled. However, the anatomical location of the so-called food entrainable oscillator is still unknown, and it might be a neuronal network rather than a single location (reviewed in [85]). Importantly, mistimed food intake has a variety of negative metabolic consequences, such as predisposition to obesity [86,87].

2.5.3. The Sleep Wake Cycle

The sleep/wake cycle is the most prominent behavioural circadian rhythm. Sleep is also critically regulated by a homeostatic drive that increases with extended waking and dissipates by sleep (reviewed in [88]) and a complex process involving many brain regions and a network of wake- and sleep-promoting neurons (reviewed in [89], see below). During sleep, changes in cortical electrical activity, detectable by electroencephalography (EEG), occur and are classified as rapid eye movement (REM) sleep and non-REM sleep. The EEG during REM sleep is similar to the awake state, but with a loss of muscle tone, REMs, and active dreams. Non-REM sleep is divided into four stages representing a continuum of relative depth characterized by distinct EEG patterns and physiology. Stage 1 plays a role in the transition from wake to sleep, and stage 2 is characterized by mixed-frequency cortical activity and the presence of sleep spindles, which might be important for memory consolidation [90]. Stages 3 and 4 are collectively referred to as slow-wave sleep (SWS) because of the amplitude slow-wave cortical activity (reviewed in [91]). SWS plays an important role in the consolidation of hippocampus-dependent spatial memory [92]. During a sleep episode, REM sleep and non-REM sleep alternate in cycles (reviewed in [91]). Sleep has multiple functions besides memory consolidation and regeneration, including metabolite clearance (reviewed in [93]). In the current model, the major purpose of sleep is to restore structural and functional synapse homeostasis [94,95]. Moreover, the clearance of interstitial solutes in the brain, provided by the glial-lymphatic (=glymphatic) system, correlates with the prevalence of slow-wave sleep [96,97]. Importantly, glymphatic clearance might provide a link in the causal relationship between sleep disturbances and symptomatic progression in neurodegenerative diseases (reviewed in [98]). Sleep deprivation and insomnia have many negative consequences, including increased anxiety, decreased attention, and impaired executive function and cognitive performance [99,100]. Light has different effects on sleep and alertness in diurnal and nocturnal species (reviewed in [101]). In diurnal species, light increases arousal and alertness. In nocturnal species, the response also depends on the wavelength: blue light (470 nm) results in delayed sleep onset, light aversion, and elevated plasma corticosterone (see above), while green light (530 nm) of the same intensity leads to reduced arousal and sleep induction [102].

The brain circuitry that governs sleep and wakefulness/arousal include cell groups in the brain stem, hypothalamus, thalamus, and basal forebrain (reviewed in [103]) (Figure 2). The ascending reticular activating system (ARAS) in the brain stem is responsible for the control of wakefulness and sleep–wake transition. Cholinergic neurons of the ARAS activate the unspecific thalamus, which controls general cortical activity, and the specific thalamus, which controls the transmission of sensory information to the cortex. In addition, cortical activity is directly and indirectly modulated by a variety of brain stem nuclei, which employ different neurotransmitters, including the noradrenergic locus coeruleus, the dopaminergic ventral tegmental area, and the serotoninergic raphe nuclei. By interacting with other brain stem nuclei, the ARAS also modulates muscle tone, as well as autonomic functions, such as breathing, heart rate, and blood pressure during wake and sleep. Sound REM sleep is associated with a silencing of the locus coeruleus promoting synaptic plasticity (reviewed in [100]). Sleep- and wake-inducing hypothalamic nuclei control ARAS activity. During sleep, the ARAS is inhibited by a system of GABAergic neurons in which the ventrolateral preoptic nucleus (VLPO) of the hypothalamic preoptic region plays a key role [104]. Consistently, the largest class of sleep-promoting drugs/anaesthetics, including barbiturates, benzodiazepines, and chloral hydrate, enhances the activity of GABA receptors (reviewed in [103]). Orexin neurons in the lateral hypothalamus and histamine neurons in the tuberomamillary nucleus are mutually connected with the VLPO and the ARAS and synergistically regulate different aspects of the waking stage (reviewed in [105]). Orexin neurons project widely into other nuclei in the hypothalamus and into the forebrain, the thalamus, and the brain stem [106,107], indicating the complex role of the neuropeptide in autonomic, neuroendocrine, and cognitive function and emotion. Orexin might also convey an efferent signal to the food-entrainable oscillator [108]. An important driver of homeostatic sleep regulation is the neuromodulator adenosine, accumulating during wakefulness in the extracellular space as a by-product of neuronal metabolic activity [109]. Consistently, caffeine, the world‘s most widely consumed psychoactive drug, induces wakefulness, the release of norepinephrine, dopamine, and serotonin in the brain, and an increase in serum catecholamine levels by blocking adenosine receptors (reviewed in [110]). Glutamatergic neurons and, to a lesser extent, cholinergic neurons in the basal forebrain contribute to the adenosine-mediated control of sleep homeostasis [111]. For the control of the circadian rhythm in sleep/wakefulness projections of the SCN to the dorsomedial hypothalamus via the subparaventricular zone (SPZ) of the hypothalamus seem to play a major role (reviewed in [103]). Interestingly, the SPZ seems to have an amplifying and integrative role in the regulation of circadian rhythms in sleep, activity, and core body temperature, but with distinct subpopulations controlling the rhythms in body temperature or sleep/wake and locomotor activity [112]. Neurons in the dorsomedial hypothalamus project to the VLPO and the lateral hypothalamus using inhibitory and excitatory neurotransmitters orchestrating rhythmic changes in sleep–wake and wake–sleep transitions (reviewed in [103]). Importantly, the SPZ, the LH, and the VLPO receive direct innervation from the ipRGCs, so activation of the VLPO might account for light-induced sleep in nocturnal animals (reviewed in [113]).

Figure 2. Simplified summary of the effects of light and the suprachiasmatic nucleus (SCN) on the brain circuitry that governs sleep and wakefulness. The cholinergic ascending reticular activating system (ARAS) is a key element in the control of wakefulness and sleep–wake transition. It activates the thalamus, which controls general cortical activity and transmission of sensory information to the cerebral cortex. By interacting with other brain stem reticular nuclei, the ARAS also modulates muscle tone as well as autonomic functions during wake and sleep. In addition, cortical activity is indirectly (via the ARAS) and directly (not shown) modulated by a variety of brain stem nuclei, which employ different neurotransmitters, including the noradrenergic locus coeruleus, the dopaminergic ventral tegmental area, and the serotoninergic raphe nuclei. Sleep- and wake-inducing hypothalamic nuclei control ARAS activity. During sleep and wake, the ARAS is inhibited and activated by a system of GABAergic neurons in the ventrolateral preoptic nucleus (VLPO) and of histaminergic neurons in the tuberomamillary nucleus (TMN), respectively. Orexinergic neurons in the lateral hypothalamus (LH) contribute to arousal by projections into the TMN, the forebrain, the thalamus, and the brain stem. The circadian rhythm in sleep/wakefulness is controlled by the suprachiasmatic nucleus (SCN) which projects to the dorsomedial hypothalamus (DMH) via the subparaventricular zone (SPZ). DMH neurons project to the VLPO and the lateral hypothalamus using inhibitory and excitatory neurotransmitters orchestrating rhythmic changes in sleep–wake and wake–sleep transitions. Importantly, the SCN, the SPZ, the LH, and the VLPO receive direct innervation from the retina. Diencephalic, brain stem, and telencephalic brain regions are assembled in red, grey and green boxes, respectively. ACh, acetylcholine. Based on [103,104,105,113].

Sleep architecture is altered in mice with a compromised molecular clockwork even under LD 12:12 conditions. In Bmal1-deficient mice, the rhythms in total sleep time, REM and non-REM sleep, and core body temperature are blunted [59]. During sleep deprivation, Bmal1-defiecient mice show a reduced propensity for sustained wakefulness/higher sleep pressure and a reduced percentage of REM sleep during recovery [59]. Similarly, in Cry1/Cry2 double mutants, the rhythms in REM and non-REM sleep are blunted and show high non-REM sleep pressure [67]. In Per2 and Per1/2 double mutants, the acrophase of rhythmic core body temperature is advanced, while the amplitude during the dark/active phase is reduced, and these mutants are more awake and have less REM sleep during the mid-third of the light phase [114]. Collectively, these data indicate an important role for clock genes in sleep pressure and sleep phase timing. Consistently, it has been suggested that insomnia is associated with polymorphisms in clock genes and clock-associated genes, such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a rhythmically expressed transcriptional coactivator that regulates energy metabolism (reviewed in [100]).

2.5.4. Cognitive Performance and Emotion-Related Behaviour

Cognitive performance, as well as brain functions affecting cognitive performance, such as mood/emotion, attention/arousal, sleep, core body temperature, and executive function, show time-of-day-dependence as well as circadian rhythms (reviewed in [101]). In humans, just after the nadir in body temperature shortly before wake time, sleepiness is highest, and vigilance and cognitive performance are lowest (reviewed in [115]), indicating a strong interconnection between these parameters. Studies using ‘forced desynchrony protocols’ in which subjects sleep in non-24 h schedules show circadian rhythms in cognitive performance, even when time spent awake has been controlled (reviewed in [116]), so sleep/wake and cognitive function are interconnected and independently regulated. However, a proper alignment between sleep/wake rhythms and internal circadian time is crucial for optimal cognitive performance [117].

Cognitive performance is a function of the neocortex and depends on sensory information processed by the specific thalamus. It is strongly regulated by paleocortical and archicortical input and by multiple projections from subcortical forebrain structures, the unspecific thalamus, and the brain stem, which convey emotional states, motivation, and alertness. Of note, the amygdala is a key structure in the forebrain for processing sensory information in the context of memory, decision making, and emotional responses, such as fear, anxiety, and aggression. It receives sensory information and input from other subcortical forebrain structures and the brain stem and sends projections to the entorhinal cortex (EC), modulating learning and memory (see below), to the hypothalamus, controlling acute, and chronic responses to stress, to the thalamus, controlling attention and alertness, and to the nucleus accumbens, controlling reward-related behaviour.

Long-term memory is a three step process that consists of the acquisition of new information, consolidation of the acquired information, and the retrieval of stored information [118]. Importantly, in mice, long-term memory formation, especially training, is time-of-day-dependent with a peak during the early night [119]. Therefore, the time of day has a strong effect on the readout of tests on cognitive behaviour. The rhythm persists in constant darkness, indicating circadian-regulated memory consolidation [119]. In addition, light has a strong inhibitory effect on various cognitive functions and behavioural dimensions in mice [120,121]. Hence, for studies on cognitive function in nocturnal rodents, one should consider performing tests on behaviour and cognition in the dark phase (under LD 12:12) or in subjective night (under DD) and, thus, in the activity phase of the animals and without the disturbing influence of light.

The archicortical hippocampus is the major brain region for episodic memory formation and for the integration of temporal and spatial information enabling navigation. It integrates sensory information, as well as information about the emotional and motivational state. Cholinergic, serotonergic, noradrenergic, and dopaminergic input for the brain stem modulates hippocampal function. The hippocampus includes the dentate gyrus (DG) and the cornu ammonis (CA), which is divided into four subfields (CA1–4). The dorsal hippocampus (DH) and the ventral hippocampus (VH) are functionally and anatomically distinct regions. The DH has a high density of so-called place cells, the cellular correlate for encoding spatial information (reviewed in [122]), and serves for spatial memory and conceptual learning, while the VH is strongly connected to the amygdala and implicated in stress responses, emotional behaviour, and contextual fear learning (reviewed in [123]). Processed sensory information reaches the CA1 pyramidal neurons via direct and indirect projections from the EC. The indirect projection, called the trisynaptic circuit, includes the projection from EC to DG granule cells and from there to CA3 pyramidal cells, sending their axons, called Schaffer collaterals, to the CA1. The hippocampus shows circadian rhythms in clock gene expression [124] that are almost 180 degrees out of phase with the expression rhythms measured from the SCN [48,80]. Mice with deletions/mutations of clock genes show impaired hippocampus-dependent memory formation [124] and a reduced ability to link spatial information with the time of day [125]. Moreover, hippocampus-dependent memory training leads to an upregulation of Per1, presumably via modulating the occupancy of the Per1 promoter by the histone deacetylase HDAC3, which is also implicated in the age-related impairment of functional synaptic plasticity [126].

The cellular substrate for hippocampal learning and memory is neuroplasticity. Structural hippocampal plasticity is provided by changes in spine formation and by adult neurogenesis in the subgranular zone (SGZ) of the DG [127,128,129] which is strongly influenced by the circadian system [130]. We have shown that adult neurogenesis is affected in BMAL1-deficient mice [59,131,132]. Moreover, the fine astrocytic processes ensheathing the hippocampal mossy fibre synapse and the astrocyte actin cytoskeleton are affected in BMAL1-deficient mice [133], indicating that the molecular clockwork modulates astrocyte-neuron interaction at the structural level of the tripartite synapse. Consistently, both neurons and astrocytes show time-of-day-dependent structural and functional changes in CA1, while pyramidal neurons change the surface expression of NMDA receptors, and astrocytes change the proximity to synapses [80]. Interestingly, the activation of puringergic receptors by extracellular ATP plays an important role in neuron–glia interaction and modulates synaptic strength (reviewed in [134]). Various purinergic receptors show a time-of-day-dependent oscillation in the hippocampus [131], some in phase with the SCN [132], suggesting a general regulatory mechanism across brain regions.

Functional hippocampal neuronal plasticity is provided by long-term potentiation (LTP), defined as a persistent strengthening of glutamatergic synapses based on recent patterns of activity [135]. Mice with mutations of the clock gene Per2 show changes in the LTP of the Schaffer collateral-CA1 synapse, presumably as a result of the reduced activation of the CREB [48], which is implicated in LTP and memory formation (reviewed in [136]). Signal transduction pathways, including MAPK and CREB are implicated in amygdala- and hippocampus-dependent long-term memory consolidation in the context of fear conditioning [137,138]. In mice, MAPK activation shows a circadian oscillation with high levels during the (subjective) light phase, associated with an increased consolidation of contextual fear memory during the (subjective) light phase [139]. Similarly, mice show time-of-day-dependent changes in hippocampus-dependent memory formation [119] and retrieval [43]. Consistently, time-of-day-dependent changes in LTP occur in the rodent hippocampus (reviewed in [140]) [80]. Nocturnal rodents exposed to chronic phase shifts show a deficit in spatial learning and memory, indicating that chronodisruption affects hippocampal function [141,142]. In hamsters, this is associated with impaired adult neurogenesis and is independent of systemic glucocorticoids [142]. In Bmal1-deficient mice, impaired contextual fear and spatial memory are associated with the reduced activation of the MAPK signalling pathway [57], indicating an interconnection between the molecular clockwork and pathways implicated in the memory consolidation. Importantly, LTP is decreased in hippocampal slices from BMAL1-deficient mice, indicating that the hippocampal molecular clockwork modulates functional synaptic plasticity. In mice with a hippocampus-specific inhibition of BMAL1 function (dnBMAL1), showing a normal circadian rhythm of locomotor activity, memory retrieval is impaired [43]. This indicates that the molecular clockwork contributes to hippocampus-dependent learning. Remarkably, the retrieval deficits observed in dnBMAL1 mice seem to be due to impaired dopamine D1 and D5 receptor-dependent cAMP signal transduction [43]. In addition, phosphorylation of the AMPA-type glutamate receptor subunit GluA1, which is modulated by D1/D5 dopamine receptor activation [143], regulates AMPA receptor trafficking, and is suggested to play a crucial role in hippocampus-dependent learning and memory [144], which is reduced in dnBMAL1 mice. Hence, the molecular clockwork might control rhythms in hippocampus-dependent memory function via cAMP-dependent D1/D5 dopamine receptor signal transduction and GluA1 phosphorylation. Importantly, dopamine, which plays important roles in executive functions, motor control, motivation, arousal, reinforcement, and reward, seems to be an important mediator in maintaining circadian rhythms in many brain regions, and the loss of dopamine neurons might account for the impairment of circadian rhythms in Parkinson’s disease (reviewed in [145,146,147]). In the SCN, D1 receptor signalling is necessary for photoentrainment [148], a mechanism that employs similar signal transduction pathways as hippocampus-dependent memory consolidation. In addition, other neurotransmitters as well as hormones might have time-of-day-dependent and/or circadian effects on cognitive performance and memory formation. The rhythm in locomotor activity levels does not show a clear correlation with circadian rhythms in memory formation in various species (reviewed in [140]). Microdialysis experiments show a time-of-day-dependent fluctuation in basal levels of various neurotransmitters in the hippocampus of nocturnal rodents. Basal levels of adenosine, noradrenalin, acetylcholine, and serotonin are higher during the dark phase compared to the light phase [149]. These neurotransmitters are key regulators of synaptic plasticity in the hippocampus [150,151,152,153]. Acetylcholine release shows a strong correlation with locomotor activity [154] and the activity of thyroid hormones, which is also implicated in hippocampus-dependent learning (reviewed in [155]). Furthermore, in a recent study by McCauley and co-workers, corticosterone was identified as a key factor in regulating time-of-day-dependent changes in synaptic strength [80].

A brief light pulse applied during the dark phase enhances the consolidation of contextual fear conditioning and CA1 LTP [156], indicating that light has a strong impact on contextual fear learning in nocturnal animals. Although there is evidence that (blue) light also enhances alertness and cognitive function in humans (reviewed in [157]), the mechanism might be different from nocturnal rodents, where light represents a strong aversive stimulus. So far, little is known on the neuronal network transmitting non-visual photic information to the hippocampus. Anterograde polysynaptic tracing of retino-recipient regions identified the amygdala and the hippocampal CA1 region among many others [158]. Data by Richetto et al. [121] suggest that mesolimbic structures, such as the nucleus accumbens and the midbrain might be involved in the effect of the light phase on behavioural responses [121]. Interestingly, the chemogenetic activation of ipRGCs in dark-adapted mice evokes circadian phase resetting and increases anxiety-related behaviour similar to light exposure [159]. Moreover, it induces neuronal activation in various brain regions, including the amygdala and the unspecific thalamus, which are implicated in anxiety and arousal, respectively [159]. Thus, non-visual light information affects alertness and anxiety presumably via the unspecific thalamus and the amygdala. Interestingly, distinct ipRGC projections mediate the effects of light on learning and mood (Figure 3). The projections of the ipRGCs to the SCN mediate the effects of light on learning, which are independent of the SCN function in circadian rhythm generation. The nature of this pathway is unknown so far but may include projections of the SCN to other hypothalamic nuclei and the septal region [160] known to project to the hippocampus [9,161]. SCN-independent projections to the thalamic perihabenular nucleus drive the effects of light on emotional behaviour [11]. The perihabenular nucleus projects to the ventromedial prefrontal cortex, which is implicated in the processing of risk and fear upstream of the amygdala and in the consolidation of extinction learning [162], to the dorsomedial striatum, which is implicated in motor learning and performance (reviewed in [163]), and to the nucleus accumbens, which integrates input from the prefrontal cortex, amygdala, ventral hippocampus, and from the dopaminergic neurons of the ventral tegmental nucleus and plays a significant role in the processing of motivation, aversion, reward, and reinforcement learning and in the induction of slow-wave sleep [164]. Hence, the perihabenular nucleus seems to play an important role in mediating the effects of light on emotion/mood implicated in cognitive function and learning. This might also be relevant for the effects of light on cognition and mood in humans. In patients with major depressive disorder and bipolar depression, treatment with bright white light (>5000 lux, >30 min) during the day, known as light therapy, ameliorates the symptoms [165]. On the other hand, exposure to excessive light at night shortly before bedtime, is associated with a greater risk for depressive symptoms (reviewed in [166]). In mice, light at night induces depressive-like behaviour without disturbing circadian rhythms [167]. This effect was mediated by a projection from the ipRGCs to the perihabenular nucleus and from here to the nucleus accumbens, suggesting that this brain circuitry might also be relevant for mental health effects of the prevalent night-time illumination in the modern 24/7 society [167]. In addition, the superior colliculus, which receives direct retinal input and mediates behaviour responses to visual danger signals, projects to the reticular formation [168] and to the amygdala via the thalamic pulvinar, driving emotional responses to visual information [169]. However, little is known about the relevance of these projections for light-at-night-induced changes in brain plasticity.

Figure 3. Simplified summary of the effects of light and the suprachiasmatic nucleus (SCN) on the major brain circuitry responsible for emotion and learning.Projections of the retina to the SCN mediate the effects of light on learning presumably via indirect projections to the hippocampus. Projections of the retina to the perihabenular nucleus (PHN) mediates effects of light on emotion/mood, memory consolidation, and motor learning. The PHN projects to the ventromedial prefrontal cortex (vmPFC) and the nucleus accumbens (NAc), both are closely interconnected with the amygdala. The NAc integrates input from the vmPFC, amygdala, hippocampus and from dopaminergic neurons of the ventral tegmental nucleus (VTA). The VTA and other monoaminergic nuclei of the reticular formation (RF) project to various brain regions, including those related to learning and memory, providing emotional and motivational drive. The superior colliculus (SC) receives direct retinal input and projects to the RF and to the amygdala via the thalamic pulvinar (not shown). Visual information is transmitted from the retina to the visual cortex via the corpus geniculatum laterale (cgl) and from there to most of the cerebral cortex including the hippocampus via the entorhinal cortex (EC). Diencephalic, brain stem, and telencephalic brain regions are assembled in red, grey, and green boxes, respectively. DMS, dorsomedial striatum.

2.6. Neuropathological Conditions and Circadian Misalignment

Chronic disruption of circadian rhythms in humans, for example in shift and night work, has aversive effects on health in general (reviewed in [170]) and may even have an effect on preterm birth (reviewed in [171]). Especially excessive artificial light at night, e.g., in shift work, during repeated transmeridian travel, or from the use of illuminated electronic devices, such as mobile phones, televisions, and personal computers disrupts circadian rhythms and suppresses the production of melatonin, both these changes are light intensity and wavelength dependent [172]. In recent years, significant technical advances have been made in developing blue-free white light-emitting diodes [173], or blue light filters, such as in the night-shift mode of smartphones, that can help to prevent chronodisruption and to preserve rhythmic melatonin production. Chronodisruption is associated with higher risk for brain dysfunction, such as sleep disturbances, impaired alertness, and depression (reviewed in [174]), and impairs brain plasticity. Moreover, there is a reciprocal relationship of chronodisruption and neurological or psychiatric conditions and diseases. Psychiatric conditions, such as depressive disorders, bipolar disorder, seasonal affective disorder, and schizophrenia, are frequently associated with abnormalities in the sleep/wake cycle or in social rhythms [175,176]. Patients with Alzheimer’s disease (AD) suffer from circadian disruption, while the cause-and-effect relationship is still unclear (reviewed in [177,178]). Moreover, in mouse models for AD [179] and other synucleopathies and neurodegenerative diseases [180,181], the light input into the circadian system and thus masking and/or entrainment is impaired, thus further enhancing circadian misalignment. Hence, there is an interconnection between neuropathological conditions and the circadian system at various levels.

3. Summary

Rhythmic brain function is controlled by light and the circadian system. The SCN and its rhythmic output govern endogenous/circadian rhythms, which are entrained to the environmental light/dark cycle by retinal input. Direct and indirect retinal input is provided to many parts of the brain, contributing to light-dependent responses in a wide range of neuronal networks. At the cellular level, synaptic plasticity is modulated by a molecular clockwork in neurons and glia, which are modulated by various rhythmic neuronal, glial, and endocrine signals.

4. Conclusions and Outlook

In recent decades, great advances have been made in understanding the molecular basis of circadian time-keeping mechanisms and circadian light perception in the mammalian brain. The greatest challenge for the future will be to decipher the complex interactions and connectivity between the various components of the circadian system at the level of complex neural networks. This is mandatory for understanding not only rhythmic basic brain function, such as sleep but also higher cognitive function such as learning and memory under physiological and pathological conditions.

The cholinergic ascending reticular activating system (ARAS) is a key element in the control of wakefulness and sleep–wake transition. It activates the thalamus, which controls general cortical activity and transmission of sensory information to the cerebral cortex. By interacting with other brain stem reticular nuclei, the ARAS also modulates muscle tone as well as autonomic functions during wake and sleep. In addition, cortical activity is indirectly (via the ARAS) and directly (not shown) modulated by the noradrenergic locus coeruleus, the dopaminergic ventral tegmental area, and the serotoninergic raphe nuclei. Sleep- and wake-inducing hypothalamic nuclei control ARAS activity. During sleep and wake, the ARAS is inhibited and activated by a system of GABAergic neurons in the ventrolateral preoptic nucleus (VLPO) and of histaminergic neurons in the tuberomammillary nucleus (TMN), respectively. Orexinergic neurons in the lateral hypothalamus (LH) contribute to arousal projections into the TMN, the forebrain, the thalamus, and the brain stem. The circadian rhythm in sleep/wakefulness is controlled by the suprachiasmatic nucleus (SCN) which projects to the dorsomedial hypothalamus (DMH) via the subparaventricular zone (SPZ). DMH neurons project to the VLPO and the lateral hypothalamus using inhibitory and excitatory neurotransmitters orchestrating rhythmic changes in sleep–wake and wake–sleep transitions. Light information reaches the SCN, the SPZ, the LH, and the VLPO by direct innervation from the retina. Diencephalic, mesencephalic and telencephalic brain regions are assembled in red, grey, and green boxes, respectively. ACh, acetylcholine. Based on [103,104,105,113].

Funding

This publication was supported by an Open-Access-Publication Fund of the Heinrich Heine University, Düsseldorf, Germany.

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