Neurobiology of Circadian Rhythms Daniel J. Buysse, M.D. Professor of Psychiatry University of Pittsburgh School of Medicine Pittsburgh Mind-Body Center Short Course on Sleep Pittsburgh, PA December 8, 2006

Neurobiology of Circadian Rhythms  Significance  Terms and concepts  Properties and characteristics of circadian rhythms  Neuroanatomy of the circadian system  Molecular biology of the circadian clock

Functional significance of circadian rhythms  Fundamental property of living organisms  “Predictive homeostasis:” Matching of rest/ activity patterns and functioning to geophysical day  Virtually every physiological and mental function in human beings varies as a function of time of day

Single-occupant motor vehicle crashes Pack, Accid. Anal. and Prev., 1995

Circadian rhythms: Key terms  Period: Time to complete one cycle –Ultradian: Period shorter than a day –Circadian: Period of about a day –Infradian: Period longer than a day  Frequency: Cycles / time period  Amplitude: One-half of peak-trough difference  Phase: Timing of a rhythm relative to a reference  Acrophase: Time of maximum value

Rhythms: Terms Amplitude Period Phase Difference in phase (Phase angle) Acrophase

Examples of biological rhythms with different periodicities Ultradian Circadian Infradian

Examples of human circadian rhythms Czeisler and Khalsa, 2000 Core body temperature Urine volume Thyroid Stimulating Hormone Growth Hormone Prolactin Parathyroid Hormone Motor activity Cortisol Time

Circadian rhythms in performance Dijk and Edgar, 1999

Neurobiology of Circadian Rhythms  Terms and concepts  Properties and characteristics of circadian rhythms  Neuroanatomy of the circadian system  Molecular biology of the circadian clock

Circadian rhythms: Properties and characteristics  Entrainment: Synchronization of a rhythm to an external time cue  Zeitgeber: External (environmental) time cue  Range of entrainment: Length of days to which an organism can be entrained  Free-running: Circadian rhythm that is not entrained to zeitgebers, i.e., running at its endogenous period length  Masking: Alteration of endogenous rhythm by environmental or behavioral factors  Constant routine: Study design to examine endogenous rhythms free of masking effects of sleep, posture, activity, meals

Rest-activity rhythm in a human subject

Free-running activity rhythms in different mammalian species Moore–Ede, 1982 Mouse: period < 24 hours Monkey: period < 24 hours Human: period > 24 hours Time of Day 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 human circadian rhythms: Masking effects of sleep Czeisler and Khalsa, 2000 Core body temperature Urine volume Thyroid Stimulating Hormone Growth Hormone Prolactin Parathyroid Hormone Motor activity Cortisol Entrained Constant Routine

Sleep-wake cycle period of 28 hours Core body temperature rhythm period just over 24 hours (tau = hours) Forced internal desynchrony Czeisler 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 a nocturnal animal Phase response curve of activity to light in a nocturnal animal Moore-Ede, 1982 Circadian time (hrs) Phase advances Phase shifts Phase delays

Components of the circadian timing system Kilduff and Kushida, 1999

Anatomy of the circadian timing system: Animation

Anatomy of the circadian timing system Retinal ganglion cells Retinohypothalamic tract SCN of the hypothalamus

Anatomy of the circadian timing system Retinal ganglion cells Retinohypothalamic tract Suprachiasmatic nucleus = SCN Optic chiasm Pituitary

Effects of lesion of the suprachiasmatic nucleus (SCN) Kilduff and Kushida, 1999 Hours Days  SCN destroyed

Efferents from the SCN SCN Hypothalamus (subparaventricular, dorsomedial, posterior nuclei) Thalamus (paraventricular Nucleus) Medial preoptic area Anterior, lateral hypothalamus Lateral geniculate nucleus

Molecular mechanisms of the circadian clock: Animation

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

Regions with greater relative glucose metabolism in evening than morning Buysse, Sleep, 2004; 27:

[ 18 F] deoxyglucose PET during a.m. and p.m. wakefulness in healthy adults Buysse, Sleep, 2004; 27: Midbrain reticular formation/ Raphe Pontine reticular formation Posterior hypothalamus L Locus coeruleus R Locus coeruleus