GOODNIGHT BRAIN: THE SCIENCE OF HEALTHY...
Transcript of GOODNIGHT BRAIN: THE SCIENCE OF HEALTHY...
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.
69 3
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.
69 3
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)