GOODNIGHT BRAIN: THE SCIENCE OF HEALTHY SLEEP

Learning Objectives

• Describe the neurobiological and molecular bases of circadian rhythms and sleep-wake cycles

• Explain to patients how healthy sleep affects brain health and wellness

• Relate the neurobiology of sleep to the mechanisms of potential sleep treatment strategies

Arousal Spectrum

Stahl and Morrissette. Stahl’s Illustrated sleep and wake disorders, 2016.

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12

Circadian Rhythms Describe Events That Occur on a 24-hour Cycle

Zeitgebers

External cues to synchronize circadian rhythms:

• Light

• Melatonin

• Eating and drinking patterns

• Social interactionsVan Someren EJW et al. Sleep Med Rev 2007;11(6):465-84.

Suprachiasmatic nucleus (SCN)

Retinohypothalamic tract

Suprachiasmatic nucleus (SCN)

Retinohypothalamic tract

Pineal gland

melatonin

Processes Regulating Sleep

Awake

Stage 1

Stage 2

Stage 3

Stage 4

REM REM REM REM

Slow-wave sleep

Time of Sleep0 1 2 3 4 5 6 7 8

Sleep Cycle

Awake

Stage 1

Stage 2

Stage 3

Stage 4

REM REM REM REM

Time of sleep

0 1 2 3 4 5 6 7 8

Acetylcholine

GABA/Galanin

Dopamine

Norepinephrine

HistamineSerotonin

Hypocretin

Espana RA, Scammell TE. Sleep 2011;34(7):845-58.

Hypocretin/Orexin

• Involved in sleep/wake, addiction, compulsivity, and overeating/obesity

Stahl and Morrissette. Stahl’s illustrated sleep and wake disorders, 2016.

Molecular Clock Genes

• An intricate group of transcription factors that regulate sleep/wake cycles by turning each other on/off

• Expression waxes/wanes approximately every 24 hours

• Turn on/off expression of other genes, including those involved in sleep, metabolism, cell division, and mood

6

9 3 CLOCK (circadian locomotoroutput cycles kaput)

BMAL1 (brain and muscle ARNT-like-1)

PER (period)

CRY (cryptochrome)

REV-ERBa

ROR (retinoic acid-related orphan receptor)

Buhr ED, Takahashi JS. Handbook of Experimental Pharmacology 2013;217:3-27.

Promoter Gene

Transcription Factors Involved in the Molecular Clock

ROR REV-ERBaCryPeriod6

9 3 CLOCK

Bmal1

DNA

69 3

Heterodimers

ClockGenesAssociatedWithPsychiatricDisorders

ClockGene Disorder References

BmalBipolardisorder Mansouretal,2006;

Nievergelt etal,2006.

Clock(oritshomolog,NPAS) Bipolardisorder Benedettietal,2003;Soria etal,2010.

Depression Soria etal,2010.

Schizophrenia Takaoetal,2007.

Seasonalaffectivedisorder Johanssonetal,2003;Partonen etal,2007.

CryDepression Soria etal,2010.

Per Bipolardisorder Nievergelt etal,2006;Artioli etal,2007;Mansouretal,2006.

Depression Artioli etal,2007.

Schizophrenia Mansouretal,2006.

Seasonalaffectivedisorder Partonen etal,2007.

Rev-erba Bipolardisorder Kripke etal,2009;Severino etal,2009.

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Suprachiasmatic Nucleus Control of Sleep

Brancaccio M et al. J Neurosci , 2014;34(46):15192-9; Colwell CS. Nat Rev Neurosci 2011;12(10):553-69.

VIP: vasoactive intestinal peptide GRP: gastrin-releasing peptide AVP: arginine vasopressinPK2: prokineticin 2

SCN

CoreGRPVIP

GABA

ShellAVPPK2

GABA

Other hypothalamic

nuclei

Hypothalamus

Projections to secondary

pacemakers throughout the

brain and periphery

Misalignment Between Central and Peripheral Clocks

Green CB et al. Cell 2008;134(5):728-42; Oosterman JE et al. Am J Physiol Regul Integr Comp Physiol 2015;308(5):R337-50.

Cost and Consequences of Sleep/Wake Disorders

Cappuccio et al, 2010; Gui et al, 2013; Lallukka et al, 2014; Liu et al, 2010; Ohayon, 2012; Palma et al, 2013; Pigeon et al, 2012.

Sleep: How much is too much? Too little?

Cappuccio FP et al. Sleep 2010; 33(5):585-92; Guo X et al. Sleep Med 2013;14:324-32; Lallukka T et al. Sleep 2014;37(9):1413-25; Liu Y et al. Sleep 2013;36(10):1421-7.

Sleep/Wake Disturbances Increase Risk of Work-Related Injury

• Sleep/wake disorders affect up to 70 million people in the US

• Workers with sleep/wake problems have a 1.62 times increased risk of being injured

Uehli et al. Sleep Med Rev 2014;18:61-73.

Psychiatric Disorders

• Sleep/wake disorders may be a contributing cause or consequence of mood disorders

• High rates of depression have been reported in shift workers• As many as 63% of patients with obstructive sleep apnea have a mood

disorder

• Individuals with insomnia• 2X more likely to develop anxiety• 4X more likely to develop depression• 7X more likely to develop substance abuse disorder

• Many psychotropic agents can affect sleep/wake cycles

Culpepper. J Fam Pract 2010;59(1):S3-11; Krystal et al. 2010;71(1):32-40; Morin, Benca. Lancet 2012;379:1129-41; Rajaratnam et al. JAMA 2011;306(23):2567-78.

Synaptic Plasticity

• REM sleep may be essential for hippocampal-dependent cognitive function and synaptic plasticity

• Sleep deprivation (specifically REM sleep deprivation) affects the expression of genes involved in synaptic plasticity

• Consequences of 1 night of sleep deprivation• Similar effects to those seen with 1% blood alcohol level• 32% increase in number of errors by surgeons on a simulated

surgery

He et al. Brain Res 2011;1426:38-42; Orzel-Gryglewska. Int J Occup Med Environ Health 2010;23(1):95-114.

Neurogenesis

Orzel-Gryglewska J. Int J Occup Med Environ Health 2010;23(1):95-114; Dresler M et al. Pharmacol Ther 2014;141:300-34; Golombek DA et al. J Physiol Paris 2013;107:310-22.

Circadian Function and Alzheimer’s DiseaseLinksBetweenADandCircadianRhythmsMelatoninproductionisdecreasedwithagingandevenfurtherinADBeta-amyloidlevelsincreaseduringperiodsofwakefulnessSCNdegenerationandlossofmolecularclockgeneexpressionrhythmicityisseeninADBeta-amyloidreducesexpressionofthemolecularclockgenesthatregulatecircadianrhythmsReducedabilityoftheretinatotransmitlight(e.g.,fromcataracts)isseeninagingindividualsandpatientswithAD

Individualswithsleep/wakeandcircadiandisordershavea1.49-foldincreasedriskofdevelopingADSleep-deprivedmiceshowincreasedlevelsofinsolubletauLevelsoforexin(involvedinmaintainingwakefulness)areincreasedinpatientswithADandcorrelatewithincreasedlevelsoftauprotein.Orexinmayalsoinhibitclearanceofbeta-amyloid

Circadianrhythmdisordersmayaffectclearanceofproteins(suchasbeta-amyloid)Sleepdeprivationincreasesneuroinflammation

Hossain MF et al. Mol Neurobiol 2019; Epub ahead of print; Van Erum J et al. Sleep Med Rev 2018;40:17-27; Wu H et al. Front Neuroendocrinol 2019; Epub ahead of print.

Melatonin and Alzheimer’s Disease

Hossain MF et al. Mol Neurobiol 2019; Epub ahead of print.

Cardiometabolic Consequences• Sleep deprivation is associated with:

• Obesity and diabetes • Decreased levels of leptin (anorectic hormone)• Impaired ability to lose weight

• Shift work is associated with cardiovascular disease, obesity, and type 2 diabetes• The prevalence of cardiovascular disease is higher in patients with restless leg

syndrome• 83% of patients with drug-resistant hypertension have obstructive sleep apnea

(OSA)• 28% of patients with type 2 diabetes have OSA• 77% of obese patients have OSA• Obesity is a risk factor for insomnia to become chronic

Froy. Endocr Rev 2010;31(1):1-24; Green et al. Cell 2008;134(5):728-42; Miletic, Relja. Collegium Antropologicum 2011;35(4):1339-47; Norman et al. J CA Dent Assoc 2012;40(2):141-9; Vgontzas et al. Sleep 2012;35(1):61-8.

Cardiometabolic Consequences (cont’d)• Many hormones involved in metabolism (e.g., ghrelin, leptin) exhibit circadian

oscillation– The expression of these hormones is regulated by molecular clock

genes/transcription factors– Many of these hormones also regulate the expression of molecular clock

genes/transcription factors

• CLOCK polymorphisms are associated with an increased risk of obesity and metabolic syndrome

• BMAL1 polymorphisms are associated with susceptibility to hypertension and type 2 diabetes

• Chronic misalignment of feeding cycles and sleep cycles results in metabolic disorders and DNA damage

Froy. Endocr Rev 2010;31(1):1-24; Green et al. Cell 2008;134(5):728-42; Takahashi et al. Nat Rev Genetics 2008;9(10):764-75.

Cancer

• Shift workers have a higher incidence of cancer

• Several cell cycle genes (e.g., MYC, WEE1) are regulated by molecular clock genes/transcription factors

• PER interacts with proteins involved in the DNA damage response

• PER expression is deregulated in breast cancer cells

• DNA damage can also act as a zeitgeber (reset the molecular clock)

• Circadian rhythm/cell cycle synchronization may prevent DNA replication during times of high exposure to damaging UV rays or byproducts of intense metabolism

Walsh et al. Sleep Med 2009;10:859-64; Takahashi et al. Nat Rev Genetics 2008;9(10):764-75.

Cancer

Takahashi S et al. Nat Rev Genetics 2008;9(10):764-75; Masri S et al. Curr Opinion Oncology 2015;27:50-6; Sahar S, Sassone-Corsi P. Nature 2009;9:886-96.

WEE1 ensures that cells are large enough to divide

MYC induces cell proliferation

P53 senses DNA damage

Cyclin D drives cell proliferation

S: synthesisG: growthM: mitosis

Cancer and Circadian Rhythms

MYC

p53Cyclin D

Wee1

Takahashi S et al. Nat Rev Genetics 2008;9(10):764-75; Masri S et al. Curr Opinion Oncology 2015;27:50-6; Sahar S, Sassone-Corsi P. Nature 2009;9:886-96.

Sleep and Immunity

Cermakian N et al. Chronobiol Int 2013;30(7):870-88; Dresler M et al. Pharmacol Ther2014;141:300-34; Golombek DA et al.J Physiol Paris 2013;107:310-22..

Sleep and Obesity

FroyO. Endocr Rev 2010;31(1):1-24; Orzel-Gryglewska J. Int J Occup Med Environ Health 2010;23(1):95-114; Golombek DA et al. J Physiol Paris 2013;107:310-22; Thaiss CA et al. Cell 2014;159:514-29.

Nutrition and the Molecular Clock

Eckel-Mahan KL et al. Cell 2013;155(7):1464-78.

CLOCK: circadian locomotor output cycles kaput BMAL1: brain and muscle ARNT-like protein Per: period Cry: cryptochromeREV-ERBa: nuclear hormone receptor-related proteinDbp: albumin D element-binding proteinNampt: nicotinamide phosphoribosyltransferase Upp2: uridine phosphorylase 2

Promoter GeneDNA 6

9 3

DbpNamptUpp2PerCryREV-ERBa

BMAL1

CLOCK

High-fatdiet

Sleep/Wake Issues in the Military

• Military members are often subject to a number of situations/issues that impact sleep duration and quality

• Reduced sleep• 60% get 6 hours of sleep or less

• Early mornings• e.g., 4am

• Shift work• 24-hour operations

• Less-than-optimal sleep conditions• Loud noises• Excessive lighting

• May have unique impacts in the military population• e.g., for every hour of sleep lost, combat effectiveness is lowered by 15-20%

Good CH et al. Neuropsychopharmacol 2019; Epub ahead of print.

Sleep deprivation

Sleep/Wake Issues Consequential Impairments

Sample Military Duties Affected

Restricted sleep (<6 hrs)

Insomnia

Interrupted sleep

Circadian rhythm disorders (e.g., 4 am

wake time)

Shift work

Cognition

Memory

Vigilance

Risk of PTSD and other psychiatric disorders

Continued sleep/wake issues after

deployment/retirement

Metabolic/endocrine issues

Personal safety

Unit performance

National security

Marksmanship

Pilot errors

Excessive daytime sleepiness

Sleep Hygiene

No disturbances

Cool environment

Sleep Time Wake Time

Activity

Dark room

No stimulants before bed

Theoretical Pharmacological Targets

Espana RA, Scammell TE. Sleep 2011;34(7):845-58.

• To promote wakefulness

• Inhibit• GABA• Galanin

• Enhance• DA• NE• 5HT• Hcrt• ACh• HA

• To promote sleep

• Inhibit • DA• NE• 5HT• Hcrt• ACh• HA

• Enhance• GABA• Galanin

Melatonin

• Endogenous melatonin is secreted by the pineal gland during periods of darkness

• Acts on the suprachiasmatic nucleus to regulate circadian rhythms

• Melatonin may help to adjust circadian rhythms if taken 3 hours before dim-light melatonin onset

Stahl and Morrissette. Stahl’s illustrated sleep and wake disorders, 2016.

Caffeine• Both adenosine 2A receptors

and dopamine D2 receptors are localized on GABAergic neurons in the striatum

• When adenosine stimulates adenosine 2A receptors it reduces the affinity of nearby D2 receptors for dopamine

• By blocking adenosine from binding to adenosine 2A receptors, caffeine prevents the lowered affinity of D2 receptors for dopamine, resulting in enhanced dopaminergic neurotransmission

Stahl and Morrissette. Stahl’s illustrated sleep and wake disorders, 2016.

Summary

• The neurobiology and molecular underpinnings of sleep are complex

• Disordered sleep/wake cycles affect many physiological and psychological functions

• As our understanding of the neurobiology of sleep increases, we are beginning to recognize how sleep/wake issues may increase risk of cancer, cardiovascular disease, psychiatric disorders, etc.

• In addition to attaining proper sleep hygiene, there are many neurobiological targets that can enhance sleep or wakefulness

Posttest Question 1

Paul is a 21-year-old college student who is interested in using over-the-counter melatonin to help with his sleep-wake cycle while studying for final exams. Which of the following statements is true regarding endogenous melatonin?

1. Melatonin is released from the pineal gland during periods of darkness

2. Melatonin is released from the pineal gland during periods of light

3. Melatonin is released from the suprachiasmatic nucleus during periods of darkness

4. Melatonin is released from the suprachiasmatic nucleus during periods of light

Posttest Question 2

Mitchell is a 42-year-old patient with shift work sleep disorder (SWSD) who reports that he is having difficulty in his job as a police officer due to excessive sleepiness during his shift. Which of the following is a potential therapeutic mechanism to promote wakefulness?

1. Inhibit hypocretin activity2. Promote GABA activity3. Promote histamine activity4. All of the above5. None of the above

Posttest Question 3

Diane is a 54-year-old Air Force veteran who suffers with insomnia. Her clinician has suggested initiating the hypocretin/orexin antagonist, suvorexant. Endogenous hypocretin/orexin has which of the following effects?

1. Decreases serotonin release from the raphe nucleus2. Decreases GABA release from the striatum3. Increases release of dopamine from the ventral tegmental

area (VTA)4. Decreases release of glutamate from the prefrontal cortex

(PFC)