Neurobiology of Circadian RhythmsNeurobiology of Circadian Rhythms

Daniel J. Buysse, M.D.Daniel J. Buysse, M.D.Professor of PsychiatryProfessor of PsychiatryUniversity of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicinebuyssedj@upmc.edu

Pittsburgh Mind-Body Center Short Course on SleepPittsburgh Mind-Body Center Short Course on SleepPittsburgh, PAPittsburgh, PADecember 8, 2006December 8, 2006

Neurobiology of Circadian RhythmsNeurobiology of Circadian Rhythms

SignificanceSignificance Terms and conceptsTerms and concepts Properties and characteristics of circadian Properties and characteristics of circadian

rhythmsrhythms Neuroanatomy of the circadian systemNeuroanatomy of the circadian system Molecular biology of the circadian clockMolecular biology of the circadian clock

Functional significance of circadian rhythmsFunctional significance of circadian rhythms

Fundamental property of living organismsFundamental property of living organisms ““Predictive homeostasis:” Matching of rest/ activity Predictive homeostasis:” Matching of rest/ activity

patterns and functioning to geophysical daypatterns and functioning to geophysical day Virtually every physiological and mental function in Virtually every physiological and mental function in

human beings varies as a function of time of dayhuman beings varies as a function of time of day

Single-occupant motor vehicle crashesSingle-occupant motor vehicle crashesPack, Pack, Accid. Anal. and PrevAccid. Anal. and Prev., 1995., 1995

Circadian rhythms: Key termsCircadian rhythms: Key terms

PeriodPeriod: Time to complete one cycle: Time to complete one cycle– Ultradian: Period shorter than a dayUltradian: Period shorter than a day

– Circadian: Period of about a dayCircadian: Period of about a day

– Infradian: Period longer than a dayInfradian: Period longer than a day FrequencyFrequency: Cycles / time period: Cycles / time period AmplitudeAmplitude: One-half of peak-trough difference: One-half of peak-trough difference PhasePhase: Timing of a rhythm relative to a reference: Timing of a rhythm relative to a reference AcrophaseAcrophase: Time of maximum value: Time of maximum value

Rhythms: Terms Rhythms: Terms

Amplitude

Period

Phase Difference in phase (Phase angle)

Acrophase

Examples of biological rhythms with Examples of biological rhythms with different periodicitiesdifferent periodicities

Ultradian

Circadian

Infradian

Examples of humanExamples of humancircadian rhythmscircadian rhythmsCzeisler and Khalsa, 2000Czeisler and Khalsa, 2000

Core body temperature

Urine volume

Thyroid StimulatingHormone

Growth Hormone

Prolactin

Parathyroid Hormone

Motor activity

Cortisol

Time

Circadian rhythms in performanceDijk and Edgar, 1999

Neurobiology of Circadian RhythmsNeurobiology of Circadian Rhythms

Terms and conceptsTerms and concepts Properties and characteristics of circadian Properties and characteristics of circadian

rhythmsrhythms Neuroanatomy of the circadian systemNeuroanatomy of the circadian system Molecular biology of the circadian clockMolecular biology of the circadian clock

Circadian rhythms: Properties and Circadian rhythms: Properties and characteristicscharacteristics

EntrainmentEntrainment: Synchronization of a rhythm to an external time : Synchronization of a rhythm to an external time cuecue

ZeitgeberZeitgeber: External (environmental) time cue: External (environmental) time cue Range of entrainmentRange of entrainment: Length of days to which an organism : Length of days to which an organism

can be entrainedcan be entrained Free-runningFree-running: Circadian rhythm that is not entrained to : Circadian rhythm that is not entrained to

zeitgebers, i.e., running at its endogenous period lengthzeitgebers, i.e., running at its endogenous period length MaskingMasking: Alteration of endogenous rhythm by environmental : Alteration of endogenous rhythm by environmental

or behavioral factorsor behavioral factors Constant routineConstant routine: Study design to examine endogenous : Study design to examine endogenous

rhythms free of masking effects of sleep, posture, activity, rhythms free of masking effects of sleep, posture, activity, mealsmeals

Rest-activity rhythm in a human subject

Free-running activity rhythms in different mammalian speciesMoore–Ede, 1982

Mouse:period < 24 hours

Monkey:period < 24 hours

Human:period > 24 hours

Time of Day 0 12 24 12 24

Periods of activity are “double-plotted,” i.e., each day is shown twice: Once to the right, and once below the previous day

Entrainment by zeitgebers in a human subject Moore-Ede, 1982

Time of Day (hours)

Scheduled rest-activity

Unscheduled “free-running”

Scheduled light-dark schedule

Unscheduled “free-running”

Scheduled light-dark schedule

Examples of humanExamples of humancircadian rhythms: circadian rhythms: Masking effects of Masking effects of sleepsleepCzeisler and Khalsa, 2000Czeisler and Khalsa, 2000

Core body temperature

Urine volume

Thyroid StimulatingHormone

Growth Hormone

Prolactin

Parathyroid Hormone

Motor activity

Cortisol

Entrained Constant Routine

Sleep-wake cycle period of 28 hours

Core body temperaturerhythm period just over 24 hours (tau = 24.17 hours)

Forced internal desynchronyCzeisler and Khalsa, 2000

Enforced 28-hour sleep-wake cycle is beyond the range of entrainment. As a result, sleep-wake cycle and core body temperature rhythms have different period lengths, i.e., are desynchronized.

Phase response curve of activity to light in Phase response curve of activity to light in a nocturnal animal a nocturnal animal Moore-Ede, 1982

Circadian time (hrs)

Phase advances

Phase shifts

Phasedelays

Components of the circadian timing system Kilduff and Kushida, 1999

Anatomy of the circadian timing system: Anatomy of the circadian timing system: AnimationAnimation

Anatomy of the circadian timing systemAnatomy of the circadian timing systemRetinal ganglion cells

Retinohypothalamic tractSCN of thehypothalamus

Anatomy of the circadian timing systemAnatomy of the circadian timing system

Retinal ganglion cells

Retinohypothalamic tract

Suprachiasmatic nucleus = SCN

Opticchiasm Pituitary

Effects of lesion of the suprachiasmatic nucleus (SCN) Kilduff and Kushida, 1999

Hours

Day

s

SCN destroyed

Efferents from the SCNEfferents from the SCN

SCN

Hypothalamus (subparaventricular,

dorsomedial, posterior nuclei)Thalamus (paraventricular

Nucleus)

Medial preopticarea

Anterior, lateralhypothalamus

Lateral geniculatenucleus

Molecular mechanisms of the circadian Molecular mechanisms of the circadian clock: Animationclock: Animation

Genetic and molecular mechanism of circadian rhythm control Pace-Schott and Hobson, 2002

Genetic and molecular mechanism of circadian rhythm control Pace-Schott and Hobson, 2002

Regions with greater relative glucose Regions with greater relative glucose metabolism in evening than morning metabolism in evening than morning Buysse, Buysse, SleepSleep, 2004; 27:1245-54, 2004; 27:1245-54

[[1818F] deoxyglucose PET during a.m. and p.m. F] deoxyglucose PET during a.m. and p.m. wakefulness in healthy adultswakefulness in healthy adults Buysse, Buysse, SleepSleep, 2004; 27:1245-54, 2004; 27:1245-54

Midbrain reticularformation/ Raphe

Pontine reticularformation

Posterior hypothalamus

L Locuscoeruleus

R Locuscoeruleus