People whose sleep pattern goes against their natural body clock are more likely to have depression


People whose sleep pattern goes against their natural body clock are more likely to have depression and lower levels of wellbeing, according to a largescale new study.

Research led by the University of Exeter, published in Molecular Psychiatry, also found the most robust evidence to date that being genetically programmed to be an early riser is protective against major depression, and improves wellbeing. Researchers suggest this may be because society is set up to be more aligned to early risers, through the standard 9-5 working pattern.

COVID-19 has led to more flexible working patterns and this research may help make the case for more adaptable working habits to suit individuals’ needs.

The team built on previous research which mapped 351 genes linked to being an early riser, or a night owl. They used a statistical process called Mendelian Randomisation to examine whether these genes were causally associated with seven mental health and wellbeing outcomes, including major depression, using data on more than 450,000 UK adults from UK Biobank’s biomedical database and research resource. As well as the genetic information, participants also completed a questionnaire on whether they were a morning person or an evening person.

The team also developed a new measure of “social jetlag” that measures the variation in sleep pattern between work and free days. They measured this in more than 85,000 UK Biobank participants for whom sleep data was available, via wrist-worn activity monitors. They found that people who were more misaligned from their natural body clock were more likely to report depression and anxiety and have lower wellbeing.

Lead author Jessica O’Loughlin, of the University of Exeter, said: “We found that people who were misaligned from their natural body clock were more likely to report depression, anxiety and have lower wellbeing. We also found the most robust evidence yet that being a morning person is protective of depression and improves wellbeing.

We think this could be explained by the fact that the demands of society mean night owls are more likely to defy their natural body clocks, by having to wake up early for work.”

Overall, the research team found that morning people were more likely to be aligned to their natural body clock. They then tested the effect by looking at shift workers, and found that morningness may not be protective for depression in shift workers, meaning morning people who work shifts may not have improved mental health and wellbeing, however, this was inconclusive.

Senior author Dr. Jessica Tyrrell, of the University of Exeter, said: “The COVID-19 pandemic has introduced a new flexibility in working patterns for many people. Our research indicates that aligning working schedules to an individual’s natural body clock may improve mental health and wellbeing in night owls.”

The study is entitled “Using Mendelian Randomization methods to understand whether diurnal preference is causally related to mental health,” and published in Molecular Psychiatry.

Life on this planet is adapted to the 24-hour (h) solar day. Over evolutionary time, the predictable daily cycles of light and dark have been internalized in the form of circadian rhythms. Circadian (circa = about; dies = day) rhythms allow synchronization of biological and behavioral processes to the external temporal environment.

Thus, optimal timing of physiological events is coordinated by these internal timekeepers. Endogenous circadian rhythms have a period of ~24 h and are reset on a daily basis to precisely 24 h through exposure to light–dark cues. Over the past century, however, the boundaries between day and night have been obscured by the widespread adoption of electric light at night. As a result, behavioral health and psychiatric consequences of circadian disruption by light at night are becoming increasingly apparent1,2.

The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Finally, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

Before electric lights were introduced about a century ago, people were exposed to minimal light at night. A full moon on a clear night illuminates the temporal zone environment 0.1–0.3 lux3, or up to 1.0 lux in the tropics4. From a meter in distance, a single candle only produces ~1.0 lux of light. The invention of electric lights near the end of the 19th century was a welcomed advance and their popularity grew rapidly5. For the first time in history, humans could extend the day resolving their fears of night-time crime, fire, and the supernatural5.

The economic benefits of electric lighting soon ensued as night shift work was introduced. By the end of the 20th century, technology provided people with additional sources of night-time light, including television, computer screens, e-readers, smartphones, and tablet computers. Today, >80% of humans and 99% of those living in the US or Europe experience significant night-time light pollution6; indeed, the artificial night sky glow is sufficiently bright that two-thirds of Europeans and nearly 80% of North Americans cannot see the Milky Way6. Importantly, between 15 and 20% of people in industrial societies work night shifts; these individuals serve as the proverbial ‘canaries in a coal mine’ for how disrupted circadian rhythms affect health.

Night shift workers suffer several health disparities compared to their day shift worker counterparts; e.g., night shift workers display increased rates of several types of cancer, elevated incidence of cardiovascular and metabolic disorders, as well as increased prevalence of behavioral health and psychiatric disorders7–9. Even those who do not work night shifts are exposed to nightly light pollution from other sources9,10. Light intensities from an average urban street ranges between 5–15 lux and a typical living room is illuminated nightly between 100–300 lux; electronic tablet computers emit ~40 lux, depending on the size of the screen10. Remarkably, 36% of adults and 34% of children sleep with a light-producing electronic device, such as a television or computer11. Again, pervasiveness and intensity of nighttime light exposure is unprecedented in our history.

Exposure to light at night perturbs the circadian system because light is the major entraining cue used by the body to discriminate day from night. When exposure to light is mistimed or nearly constant, biological and behavioral rhythms can become desynchronized, leading to negative consequences for health. The relationship among mood disorders, light, and circadian rhythms have long been recognized9. One example is seasonal affective disorder in which mood oscillates between dysthymia during the short day lengths of winter and euthymia during the long summer days. Indeed, many mood disorders are either characterized by sleep and circadian rhythm disruption or precipitated by an irregular light–dark cycle. Sleep disruption is a diagnostic criterion for major depression, bipolar disorder, post-traumatic stress disorder, generalized anxiety, and other mood disorders12.

Shift work disorder (SWD) is a circadian rhythm sleep disorder associated with working outside of the typical 800 to 1700 h shifts13. Individuals with SWD report insomnia, difficulty falling asleep, and experiencing excessive sleepiness or micro-naps when it is important to be alert and productive14. Affective responses associated with SWD include irritability, depression, and difficulty maintaining personal relationships.

Shift work disorder can be provoked by night shifts, rotating shifts, afternoon shifts, or even early morning shifts. SWD is associated with chronic sleep deprivation and a persistent “sleep debt”15. Such chronic sleep loss has serious consequences for health, productivity, and safety. Pharmacological treatments for SWD have largely been ineffective16, although proper timing of caffeine has been reported to improve alertness for people working simulated night shifts17. Melatonin appears to improve adaptation to day-time sleep schedules and increases the length of sleep16,17. However, separating out the effects of circadian rhythm disruption from sleep disruption on mood disorders often requires studies on nocturnal animals as most studies on humans cannot parse the two factors9.

In addition to light at night, circadian rhythms can be disrupted by another modern convenience, jet travel across time zones. Jet lag, also called jet lag disorder, is a transient sleep problem that arises when an individual travels across multiple time zones18. Because circadian rhythms do not instantaneously reset, for several days they may remain more closely entrained to the original time zone than the current time zone; the lag in synchronizing these internal rhythms to the current photic (light) and non-photic (social interactions, timing of meals, etc.) cues results in disturbed sleep, daytime fatigue, hormone profiles, gastrointestinal issues, and changes in mood.

These symptoms are all manifestations of a misaligned circadian system. People who regularly cross multiple time zones, such as international flight crews, often report persistent jet lag symptoms; negative symptoms typically increase with the number of time zones crossed and are worse for travelers flying in an eastern direction than a western direction due to the necessity to advance the body’s clock19,20.

Several studies have suggested that mood changes, especially dysphoric mood, are an important aspect of jet lag21. For example, a study of five men experiencing 7-h phase shifts (one westward shift and one eastward shift) over the course of a month reported that the eastward shift significantly disrupted sleep and elevated anxiety and depression scores20.

Although scientific studies have focused primarily on the health consequences of “jet lag” caused by air travel across time zones, a much greater proportion of the population regularly experiences ‘social jet lag’, which is a related phenomenon in which individuals remain in their time zone but significantly shift their sleep-wake patterns several days per week22.

Indeed, social influences on sleep time commence as children begin day care or school— parents often enforce a set bedtime and awakening during the school week, but then allow their children stay up later and sleep later to resolve sleep debts on weekends and vacations22. A large scale epidemiological study confirmed that both sleep timing and duration are substantially challenged by work and school schedules or other social events. To align sleep and wake times with social obligations, 80% of the population uses alarm clocks on school or work days23. Early school and work schedules are particularly difficult for individuals with late chronotypes (i.e. “evening larks” with late sleep periods).

Social influences on the timing of human sleep becomes apparent when comparing sleep–wake behavior on work and free days. The vast majority of people display clear differences in both sleep duration and timing; sleep duration shortens significantly (by ~2 h/night) from the age of 10–1722, reflecting reduced sleep during school or work days. The profound mismatch between the “enforced” sleep duration on school/work days and the variable sleep duration on days off demonstrates the strong effect of social times on daily sleep behavior.

Although only ~20% of individuals in Europe and North America work night shifts, and a much smaller proportion of individuals experience chronic jet lag, virtually everyone experiences circadian disruption provoked by social jet lag, and the associated change in the timing of light exposure.

In sum, lifestyle changes that have occurred in response to technological advances over the past century have resulted in unprecedented changes in the timing and duration of light exposure, which in turn has the potential to desynchronize circadian rhythms; increased prevalence of disrupted circadian rhythms strongly correlates with the increased incidence of mood disorders9,24–26. Notably, neural systems associated with affect, such as the limbic brain regions, monoamine neurotransmitters, and the hypothalamic–pituitary–adrenal axis (HPA), are all under circadian regulation27–31. Thus, it is reasonable to expect that widespread disruption of circadian rhythms would contribute to the prevalence of mood disorders9,32,33.

Light detection and circadian rhythms

In addition to the image forming photoreceptors (rods and cones) in the retina, light is also detected by specialized photoreceptor cells in mammals. This third class of photoreceptors, called intrinsically photosensitive retinal ganglion cells (ipRGCs), are engaged in several non-image-forming functions, including circadian phototransduction34. The ipRGCs constitute a small fraction of the larger class of retinal ganglion cells, but their expression of melanopsin, a photopigment, makes them exquisitely photosensitive34,35. Blue light (~480 nm) most strongly stimulates the melanopsin photopigment ipRGCs, whereas red light (>600 nm) has minimal effect35.

The characteristics of sunlight change across the day and in response to the atmosphere; typically, sunlight contains more short (blue) wavelengths during the day and then shifts to longer (red) wavelengths toward sunset. The sensitivity spectrum of melanopsin may be an adaptation to the natural solar cycle, so that ipRGCs are tuned to discriminate daylight from evening, allowing better entrainment of circadian rhythms9. When exposed to light in the activating spectrum, ipRGCs propagate neural impulses via the retinohypothalmic tract directly to the circadian master clock, the mammalian suprachiasmatic nucleus (SCN) of the hypothalamus.

This monosynaptic pathway conveys photic information via the release of excitatory amino acids, namely, glutamate. Activation of the SCN via light results in Ca2+ influx and activation of intracellular signaling cascade; Ultimately, leading to increased expression of Period genes to set the molecular clock36. In addition, ipRGCs have other direct and indirect targets throughout the brain, including mood-related structures (e.g. amygdala and habenula)37.

The SCN molecular clock comprises a set of transcriptional–translational feedback loops that drive rhythmic 24-h expression of the core canonical clock components38,39. In the primary feedback loop, circadian locomotor output cycle kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1) proteins form heterodimers in the cytosol of cells of the SCN. The CLOCK-BMAL1 complex translocates to the nucleus and binds to regulatory elements of the DNA containing E-boxes, which in turn activate expression of period (PER1, PER2, and PER3) and cryptochrome (CRY1 and CRY 2) genes.

PER and CRY proteins then heterodimerize and translocate into the nucleus, where they repress their own transcription by acting on the CLOCK-BMAL1 complexes. In mice, activation of CLOCK-BMAL1 occurs in early morning leading to the transcription of PER and CRY protein in the early afternoon and subsequent repression of CLOCK-BMAL1 transcription in the evening/night39. In an interacting feedback loop, CLOCK-BMAL1 complexes activate expression of nuclear receptors, REV-ERB α and RORα. Their protein products feedback to regulate BMAL1 by competitively binding retinoic acid-related orphan receptor response elements in the BMAL1 promoter40. REV-ERBs repress the transcription of BMAL1, whereas RORs activate it. These two loops form the basis of the molecular clock, but a complex network of interacting genes and post-translational modifications ensure that the process takes ~24 h to complete38,39. This transcriptional–translational feedback loop is the basis of the intrinsic daily circadian rhythm.

In the absence of environmental signals, the molecular clock will continue to produce ~24-h or circadian rhythms. People living in caves or bunkers without light or temperature cues will maintain circadian sleep–wake and body temperature rhythms, although they begin to free-run with a rhythm slightly longer than 24 h41. Therefore, light serves as the major entraining (synchronizing) cue to precisely maintain synchrony with the environment. Light exposure during the night phase shifts the clock transcription-translations cycle by rapidly inducing expression of Per1 or Per2, depending on whether the light occurs during the early or late night42–44.

Phase shifting can be useful for adapting to changing seasonal day lengths, or more recently travel to a new time zone, but abrupt changes or inappropriate timing of light exposure can be problematic for daily life. For example, the use of electronics during the night can unintentionally phase shift the circadian rhythm, leaving it decoupled from the natural environmental light–dark cycle45, with potentially dysregulated physiology and behavior.

The SCN functions as the central circadian oscillator, although similar intracellular clock mechanisms are expressed in other brain regions, as well as in peripheral tissues. Clocks throughout the body remain synchronized with one another by responding to signals from the SCN, either through direct neural inputs or indirect signals such as humoral, behavioral, or other physiological rhythms. For example, timing of feeding and body temperature can help synchronize peripheral oscillators46–48. Aberrant light exposure that disrupts these rhythms may drive downstream dysregulation of circadian rhythms in peripheral systems.

The two most prominent endocrine manifestations of circadian rhythms are the daily cycles of melatonin and glucocorticoids (cortisol in humans; corticosterone in most rodents). Time of day information is transmitted to the pineal gland from the SCN to regulate production and secretion of the indole amine, melatonin. Melatonin is derived from serotonin via two enzymatic steps, and then secreted from the pineal gland at night in both diurnal and nocturnal animals.

Circulating melatonin is also a cue to help entrain clocks in peripheral organs via several interactions with the molecular clock mechanism, including phase-resetting clock genes49. Cells in the periphery exposed to melatonin respond in ‘night-mode’, whereas cells not exposed to melatonin respond in ‘day-mode’. The secretion of melatonin is tightly controlled by light; <3 lux of light exposure at night is effective in suppressing the onset of melatonin secretion and shortens melatonin secretion duration in humans50,51. Thus, via suppression of melatonin rhythm, light at night has the potential to substantially alter physiology and behavior.

Additionally, the circadian system regulates glucocorticoid secretion from the adrenal glands, such that concentrations tend to peak in the morning just before awakening and decrease throughout the day in diurnal animals, including humans52,53. The reverse pattern occurs in nocturnal mammals. The functional significance of increased glucocorticoid concentrations during the active period and decreased concentrations during sleep is related to the hormone’s important role in glucose homeostasis. Glucocorticoids also subserve several physiological and behavioral responses to stress.

Given the wide range of glucocorticoid effects on biological processes that are crucial for survival, it should not be surprising that glucocorticoid concentrations are tightly regulated by negative feedback at each level of the HPA axis. Indeed, dysregulated glucocorticoid secretion is associated with several debilitating health conditions, including major depressive disorder54. Because light exposure is an important zeitgeber for the circadian rhythm of cortisol in humans, exposure to light at night could dysregulate the HPA axis, in turn increasing the prevalence of cortisol-associated mood disorders55.

Circadian rhythm disruption

Most of the evidence supporting the effects of atypical light exposure on affective responses has been gleaned from animal models, particularly rodents, because of the ease with which light exposure can be controlled. One advantage of using rodents is that the most common lab species are nocturnal, and so exposure to light at night occurs during their active and awake phase. Thus, light at night does not directly alter sleep in nocturnal species.

This is important because most effects of disrupted circadian rhythms on human mood are attributed to sleep disruption, but studies using nocturnal species demonstrate that this is not the only cause as sleep remains intact when animals are exposed to dim light at night56. Studies of light at night exposure in diurnal rodent species generally yield similar affective responses to nocturnal rodents57,58.

Another important difference between humans and individuals of some rodent species is the production of pineal melatonin. Although both nocturnal and diurnal species produce melatonin during the dark phase, several common laboratory strains of mice have no detectable pineal melatonin rhythms. Nonetheless, studies using Swiss Webster mice (which have no detectable pineal melatonin) vs. Siberian hamsters (which have a robust pineal melatonin rhythm) have reported similar effects of light at night on affective responses33,59–61. This observation suggests that suppressed melatonin by nighttime light is not the only or even primary mechanism, but still may be an important contributor in humans and a potential point of intervention.

Accumulating evidence demonstrates both direct and indirect connections between artificial light at night and mood regulation. First, exposure to light at night can directly affect mood through ipRGC projections to brain regions involved in affect62,63. Mice exposed to alternating cycles of 3.5 h light and 3.5 h dark (termed T7), which do not significantly affect cycling clock gene expression or sleep, develop depressive-like symptoms63. In contrast, mice lacking the melanopsin gene are protected against such depressive responses, suggesting the behavioral changes occur because ipRGCs project either directly or via the SCN to brain regions involved in mood regulation. In addition, there are several indirect pathways affected by light at night that may contribute to mood disturbances37.

Circadian rhythm disruption and major depressive disorder

Major depressive disorder (MDD) is characterized by alterations in mood, typically increased sadness and/or irritability that is accompanied by at least one of the following psychophysiological symptoms: alterations in sleep, sexual desire, or appetite, inability to experience pleasure, slowing of speech or actions, crying, and suicidal thoughts64. Diagnosis of MDD requires these symptoms to persist for at least two weeks and interfere with normal daily functions64. MDD affects vast numbers of people worldwide; the Global Burden of Disease Consortium examined the global incidence and prevalence for 328 diseases in 195 countries from 1990–2016, MDD ranked within the top ten leading causes of disease burden in all but four countries examined65.

The incidence of MDD worldwide is on the rise; the number of people diagnosed with depression increased by ~18% from 2005 to 201566. Notably, rates of MDD correlate with modernization of society67; which may reflect the increased circadian disruption (i.e., light at night, shift work, and jet lag) or the interaction between circadian disruption and other environmental factors experienced in modernized countries.

There are few human studies that have examined the link between circadian disruption and MDD specifically, as most human data combine all types of depression. Nonetheless, studies examining the association between shift work and MDD have produced varied results68–70. For example, in a population of ~4000 South Koreans, the prevalence of MDD among shift/night workers was significantly increased relative to daytime workers68.

Among a Brazilian cohort of ~36,000 workers, night shift work was significantly associated with MDD only in females70. No association was reported between shift work and MDD in a French study69. If all types of depression are combined, then a clear association emerges between shift work and depression13,71–73. A meta-analysis of 11 studies concluded that night shift workers are 40% more likely to develop depression relative to daytime workers13.

Human studies examining the effects of jet lag or social jet lag on MDD are sparse74. One such study, examined the amount of social jet lag (i.e., absolute difference between the midsleep on non-work days and midsleep on work days) in patients with MDD and healthy individuals. The authors concluded that there was no association between the amount of social jet lag and severity of depressive symptoms. Additionally, patients with MDD demonstrated no differences in social jet lag relative to healthy people74. However, in common with shift work, generalizing depression (i.e., combining all types of depression) results in a link between jet lag/social jet lag and depression75–79.

Human clinical data support a strong interaction between MDD and circadian processes. Symptoms of depression demonstrate diurnal variations; patients exhibit symptoms in a morning-worse or evening-worse pattern80. Patients with MDD typically express more severe symptoms in the morning, which is considered to be associated with a more severe form of depression80. Disruptions of biological rhythms underlie hallmarks of MDD; specifically, alterations in sleep/wake states (decreased latency to rapid eye movement sleep, concurrent with increased rapid eye movement sleep and reduced slow wave sleep), social rhythms, hormone rhythms (reduced amplitude in melatonin and cortisol rhythms), and body temperature rhythms (reduced amplitude and increase in nocturnal body temperature) are seen in patients with MDD81.

Clinical studies demonstrate that the severity of MDD is correlated with the degree of misalignment of circadian rhythms82. Further, examination of circadian patterns of gene expression within postmortem brains of patients with MDD demonstrate reduced amplitude, shifted peaks, and altered phase relationship between genes, particularly in canonical clock genes27.

Most successful treatments of depression, bright light therapy, wake therapy, social rhythm therapy, and antidepressants (SSRIs, SNRIS, and agomelatine) directly affect circadian rhythms83. Morning bright light therapy phase advances the rhythm in melatonin and the degree of phase advancement is correlated with the amelioration of depressive symptoms84. Additionally, administration of antidepressants (SSRIs, SNIRs, and agomelatine [MT1, MT2 agonist and 5HT2c antagonist) result in a phase advancement of circadian rhythms (i.e., melatonin, body temperature, activity, and cortisol rhythms)85,86. Wake therapy directly alters sleep-wake rhythms by increasing the amount of SWS, reducing the latency to REM sleep, and reducing the duration of REM sleep87. Thus, successful treatment of MDD with chronotherapies, as well as diurnal variation in symptoms provide evidence that circadian disruption may underlie this disease.

There is ample basic science evidence to support an association between disrupted circadian rhythms and depressive-like behavior. To assess the role of the SCN in regulating depressive-like behavior, Tataroglu and colleagues bilaterally lesioned the SCN and examined the effect on depressive-like behavior via forced swim tests88. Rats that received bilateral SCN lesions demonstrated reduced immobility.

Thus, the authors concluded that SCN lesions have a protective effect in the induction of behavioral despair88. Similar conclusions were reached almost a decade earlier when Arushanyan and colleagues demonstrated reduced immobility during the forced swim test, in rats that received bilateral SCN lesions89. It may be difficult to draw definitive conclusions from these studies as testing of depressive-like behavior occurred during the inactive phase of the rats.

SCN lesions likely disrupted the diurnal rhythm in activity; subsequent studies examining the role of the SCN in regulating depressive-like behavior have reached the opposite conclusion utilizing animals with an intact SCN83,84. Genetic disruption of circadian rhythms in the SCN via SCN-specific Bmal1-knockdown, or forced desynchrony of the SCN via exposure to a T22 light–dark cycle increased depressive-like behavior in mice and rats, respectively90,91.

Similar effects of increased depressive-like responses have been demonstrated in other rodent models of circadian disruption. Rats exposed to 8 weeks of constant light exhibit increased depressive-like behavior concurrent with loss of diurnal rhythms in activity, melatonin, and corticosterone92. Administration of agomelatine to rats exposed to 3 and 6 weeks of constant light prevented the increase in depressive-like behavior and restored diurnal corticosterone and melatonin rhythms respectively93,94.

As with constant light, exposure to dim light at night induces depressive-like behavior in multiple species of rodents58–60,95. In female Siberian hamsters, exposure to 4 weeks of dim light at night (dLAN; 5 lux) increases depressive-like responses and neuroinflammation with concurrent decreases in dendritic spine density within the hippocampus59. Treatment with a dominant-negative TNF inhibitor prevented the increase in depressive-like behavior59.

Additionally, diurnal rats exposed to dim light at night (5 lux) for 3 weeks demonstrated increased depressive-like behavior and reduced dendritic length within CA1 and dentate gyrus58. Acute (3 nights) exposure of mice to dLAN (5 lux) is sufficient to induce alterations in clock genes and increase depressive-like behavior60. However, studies have also reported no association between LAN and mood in C57Bl/6 mice suggesting a potential strain specific effect of LAN96,97. Taken together, there is substantial clinical and basic science evidence to support a link between circadian rhythm disruption and major depressive disorder.

Circadian rhythm disruption and anxiety

Although several studies have suggested that night shift work and persistent jet lag provoke anxiety, more recent analyses suggest that the mood changes may reflect disturbed sleep, rather than disturbed circadian rhythms per se. For example, a longitudinal study of day shift workers without prior sleep disturbances who transitioned to rotating shift work schedules reported elevated anxiety along with disordered sleep98. Similarly, nurses with Shift Work Disorder display elevated anxiety scores on the Hospital Anxiety and Depression Scale99. However, rapid transitions to night shift work did not affect anxiety levels in a questionnaire study of nurses100. Jet lag, accomplished by undergoing a 7-h westward time shift by jet in five men preceding the study and, 1 month later, a 7-h eastward shift preceding was associated with disrupted sleep and elevated anxiety and depression scores, especially in simulated eastward travel20.

Studies of rodents revealed relationships among the circadian system and anxiety-like disorders. For instance, targeted disruption of canonical molecular clock components alerts anxiety-like behavior. Mice with a Δ19 mutation in the Clock gene display reduced anxiety-like behavior and are less fearful of aversive stimuli than wild-type mice101.

Notably, clock regulates cholecystokinin (CCK) expression in the ventral tegmental area (VTA) and Δ19 mutation in the Clock gene is sufficient to induce manic-like behaviors102. In contrast, mice lacking both Per1 and Per2 display elevated anxiety-like behavior, whereas mice lack either Per1 or Per2 do not have altered anxiety-like responses103. Inhibition of Per1/Per2 expression in the nucleus accumbens (NAc) of wild-type mice also produces anxiety-like behavior, suggesting a causal role for these core clock components in the NAc for regulating anxiety.

Other studies have investigated how environmental disruption of circadian rhythms (e.g., via exposure to light at night) contributes to the development of anxiety-like behavior. For example, housing adult rats chronically in constant light induces anxiety-like behavioral responses92. However, the effects of light as a circadian disruptor are inconsistent across species104–108, and may depend on the developmental window during which circadian disruption occurs, as well as the type of light (i.e. halogen, compact fluorescent, or light emitting diode) and its intensity108,109.

For example, exposure to dim light at night during early development in mice increases adult anxiety-like responses108,109, whereas exposure of adult mice to light at night reduces anxiety-like responses106. Furthermore, glucocorticoid concentrations are often reduced in hamsters and unaltered in mice exposed to light at night compared to dark nights, suggesting that the affective behavioral responses to atypical lighting are not the result of elevated corticosterone60,110,111.

Mice housed in 20-h light–dark cycles, a paradigm that disrupts circadian rhythms, display reduced dendritic length and complexity in neurons of the prelimbic prefrontal cortex, associated with anxiety112. Obviously, the extent to which light exposure alters sleep differs among species of diurnal and nocturnal rodents56,113. Together these data provide modest evidence in support of an association between circadian rhythm disruption and anxiety.

reference link :

More information: Molecular Psychiatry (2021).


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