1. Olivier van Reeth, M.D. Ph.D. Centre d’Etudes des Rythmes Biologiques, Univ. Libre de Bruxelles Centre d’Etudes des Troubles du Sommeil, CHIREC Dipartimento di Neurologia e Centro di Medicina del Sonno, Univ. Catt. di Roma Interactions between stress, sleep and circadian rhythms: from clinical situations to animal models

2. Physiological adaptation response to environmental changes The STRESS system: REACTIVE adaptation to unexpected daily threatening environmental challenges The CIRCADIAN system: PREDICTIVE adaptation for expected daily environmental challenges At least two major physiological systems are involved in the adaptation of the organism to environmental challenges

3. ACTIVATION OF THE THE HPA AXIS Pituitary Hypothalamus Glucocorticod ACTH + + Adrenal Centresintégrateurs CRH/AVP Stress Adaptation/Maladaptation · Stress response, depression… Maternal Corticosterone · Regulates cerebral development in the fetus

4. THE STRESS REACTION Stimulus - Stressor Cognitive evaluation Physiological response Neuroendocrine activation Behavioral response Metabolic response Homeostatic state of the organism Successful Unsuccessful Adaptation - Maladaptation - Diseases: Ulcus Amenorrhea Anorexia Sleep disorders … Depression

5. THE CIRCADIAN TIMING SYSTEM THE CIRCADIAN TIMING SYSTEM PVN Posterior Nucleus Anterior Nucleus SCN PVN Lateral preoptic Nucleus Median preoptic Nucleus

6. Examples of human circadian rhythms Parathyroid Hormone Motor activity Core body temperature Urine volume Thyroid Stimulating Hormone Cortisol Time W 1624816 0 1 2 3 4 5 3 2 1 20 10 0 37.5 37.0 36.5 36.0 WS 25 15 16 0 32

7. Behavioral human circadian rhythms Rest - activity cycle Sleep - Wake Cycle

8. Circadian rhythms are flattened and disrupted in depressed patients        Sleep ControlDepressed 20 40 60 80 100 691215182124369 Sleep PLASMA MELATONIN (pg/mL) PLASMA CORTISOL (ng/mL) Sleep 20 70 120 170 220 691215182124369 BODY TEMPERATURE (°C) 7911131517192123791113531 37.2 37.0 36.8 36.6 36.4 36.2 36.0 Clock Time

9. Interactions Stress - Circadian Rhythms in Humans The cortisol response to awakening in relation to different challenge tests and a 12-hour cortisol rhythm. Schmidt-Reinwald A et al. Life Science, 1999. Low doses of melatonin and diurnal effects on thermoregulation and tolerance to uncompensable heat stress. McLellan T, J. Appl. Physiol., 1999. Serial CSF Corticotropin-Releasing Hormone Levels and Adrenocortical Activity in Combat Veterans With Posttraumatic Stress Disorder. Baker D. et al. Am. J. Psychiatry, 1999.

10. Behavioral circadian studies in rodents DD: Free running conditions 12/12 LD Cycle

11. The Phase Response Curve Concept

12. Phase Shifting effects of acute stress on the circadian clock: induced hyperactivity Induced locomotor activity (access to a new running wheel) at 8 different circadian times Induced Activity Control

13. Phase Response curve to induced hyperactivity Phase advances in the circadian activity rhythm during the second part of the no active phase of the animal's activity cycle Phase delays during the late part of the active phase of the animal's activity cycle Little or no effect at other phases

14. Phase shifting effects of acute stress on the circadian clock: restraint stress 3-h periods of restraint stress at 8 different circadian times:

15. The response of an organism to an acute stressor varies as a function of the time of day of stressor presentation The response of an organism to an acute stressor varies as a function of the time of day of stressor presentation The functioning of the circadian system is affected by stress, and its response to stress is a function of the time of day at which the stressor is applied. The functioning of the circadian system is affected by stress, and its response to stress is a function of the time of day at which the stressor is applied. STRONG TIME-RELATED INTERACTIONS BETWEEN THE STRESS SYSTEM AND THE CIRCADIAN SYSTEM

16. Are inter-individual differences in stress reactivity and circadian functioning related? Male rats, 2 months of age Corticosterone secretion in response to a 20-min restraint stress Running wheel activity recorded as a rhythmic behavioral marker of the circadian clock Adaptive response of the circadian system to an abrupt shift in the LD cycle was assessed (jet-lag paradigm). After resynchronisation to the LD cycle, the free running period in DD was assessed

17. Are inter-individual differences in stress reactivity and circadian functioning related? Corticosterone response to acute restraint stress Time (min) Corticosterone (ng/ml) Abrupt shift in the L/D Cycle

18. Circadian functioning is linked to stress reactivity in rats Corticosterone (C20) ng/ml Days to resynchronize Corticosterone (C20) ng/ml Free running period Corticosterone (C20) ng/ml Total daily activity

19. EFFECTS OF STRESS ON HUMAN SLEEP Sleep complaints/changes: - after disturbing life events - after disturbing life events - in chronic insomniac patients - in chronic insomniac patients - in shift workers - in shift workers - in stress-related sleep disorders - in stress-related sleep disorders - in depression - in depression

20. INTERACTIONS BETWEEN STRESS AND HUMAN SLEEP Close temporal link between HPA axis activity and sleep Close temporal link between HPA axis activity and sleep Exogenous administration of CRH, ACTH, Cortisol can alter sleep architecture Exogenous administration of CRH, ACTH, Cortisol can alter sleep architecture Role of immune system and its response to stress Role of immune system and its response to stress Sleep deprivation, as a stressor, can induce long term metabolic and cognitive consequences of glucocorticoid excess Sleep deprivation, as a stressor, can induce long term metabolic and cognitive consequences of glucocorticoid excess

21. Usual Finding in Patients with Major Depression Type of Measure Shifted from first to second non-REM period (decreased delta sleep ratio) Temporal distribution of delta activity DecreasedDelta (0.5-4.0 Hz) activity, power Shifted toward the first part of sleep period Distribution of REM sleep IncreasedREM density or REM intensity DecreasedREM sleep latency Typical EEG Sleep Finding in Patients with Major Depression (Selected Measures) REM Sleep Measures Quantitative EEG Measures

22. EFFECTS ON STRESS ON SLEEP: ANIMAL MODELS Acute restraint stress Acute restraint stress Kyoto Wistar rats Kyoto Wistar rats Prenatal stress model Prenatal stress model

23. EFFECTS OF ACUTE STRESS ON SLEEP IN RODENTS Restraint stress (30 - 120 min) Restraint stress (30 - 120 min) Restorative sleep: Restorative sleep: PS SWS ( ) Circadian factors: Circadian factors: time of day effect time of day effect altered corticosterone rhythm altered corticosterone rhythm Mechanisms: Mechanisms: − CRH Activation NorAdr − CLIP Activation 5HT − Prolactin Koehl et al, 2002

24. Wistar Kyoto Inbred Rats  Increased Immobility in the FST  Decreased activity in the OFT  Escape deficit in the learned helplessness paradigm  Depressed-like behaviors reversed with antidepressants  Abnormal 24-hour Hormonal profile  Abnormal Sleep patterns: Increased sleep fragmentation Increased wake and PS Decreased SWS WISTAR WKY

25. old 0 weaning 21 days - 21days adult 3-8 months birth 20-24 months Prenatal stress (PRS) Restraint stress 3X45 min per day during the last 11 days of the gestation THE « RESTRAINT » PRENATAL STRESS MODEL

26. PRENATAL STRESS AND BEHAVIORAL CHARACTERISATION  learning/memory disorders  drugs of abuse vulnerability  depressive-like behavior  anxiety-like behavior Circadian rhythms ? Sleep - wake cycle ?

27. Corticosterone circadian rhythm in adult male rats ) PRS Corticosterone (ng/ml) Time

28. Effects of PRS on spontaneous Sleep-Wake cycle 12 %PS 2 4 6 8 10 12 14 16 18 % W 20 30 40 50 60 70 * % SWS1 4 6 8 10 12 14 16 18 20 ** * %SWS2 20 30 40 50 60 70 *** * ** CONT PRS Time (h) 48162024 12 48162024

29. Correlation between sleep and corticosterone 4008001200160020002400 Sleep fragmentation (dark phase) 200 250 300 350 400 450 500 r = 0.57 p=0.0224 Total corticosterone (AUC) in response to restraint stress CONT PRS 4008001200160020002400 % PS (total recording time) 6 7 8 9 10 11 12 r = 0.80 p=0.0002 CONT PRS

30. Circadian entrainment under a 12/12 LD Cycle

31. Onset of activity Offset of activity Alpha duration

32. Resynchronisation of the Activity Rhythm After a 6-h Shift in the LD Cycle * Days required to resynchronize locomotor activity CONTPRS

33. DEPRESSION Anhedonia,lack of motivation Anxiety (comorbidity) Body weight changes Feeding disturbances Increased REM sleep HPA axis hyperactivity Shift of cortisol rhythm Prenatal Restraint Stress Depressive-like abnormalities : HPA axis reactivity Shift of corticosterone rhythm paradoxical sleep ACh release feeding behaviour %time open arms (Plus maze) immobility (Porsolt) Motor retardation/agitation

34. Coworkers Fuchun Lee Laurence Weibel Gioacchino Mennuni Angela Giovane Sonia Maccari Stefania Maccari Jerome Mairesse Carlo Cinque Muriel Darnaudery Charlotte Laloux Muriel Koehl (Chicago, Bordeaux) Fred Turek (NU, Chicago)