_between stress sleep and circadian rhythms how do 应力之间的相互作用睡眠和昼夜节律如何课件

Olivier van Olivier van ReethReeth , M.D. , M.D. PhPh.DD. Centre dEtudes des Rythmes Biologiques, Centre dEtudes des Rythmes Biologiques, UnivUniv. Libre de Bruxelles. Libre de Bruxelles Centre dEtudes des Troubles du Sommeil, CHIRECCentre dEtudes des Troubles du Sommeil, CHIREC Dipartimento Dipartimento di di Neurologia Neurologia e e Centro Centro di di Medicina del SonnoMedicina del Sonno , , UnivUniv. . CattCatt. di . di RomaRoma Interactions Interactions between between stress, stress, sleep and circadian rhythmssleep and circadian rhythms : : from clinical from clinical situations to animal modelssituations to animal models Physiological Physiological adaptation adaptation response response to to environmental environmental changeschanges The The STRESS system: STRESS system: REACTIVEREACTIVE adaptation to adaptation to unexpectedunexpected daily daily threatening environmental threatening environmental challengeschallenges The The CIRCADIAN system: CIRCADIAN system: PREDICTIVEPREDICTIVE adaptation for adaptation for expectedexpected daily daily environmental environmental challengeschallenges At least two major physiological systems are involved in the adaptation of the organism to environmental challenges ACTIVATION OF THE THE HPA AXISACTIVATION OF THE THE HPA AXIS PituitaryPituitary HypothalamusHypothalamus GlucocorticodGlucocorticod ACTHACTH + + + + AdrenalAdrenal Centres Centres intgrateursintgrateurs CRH/AVPCRH/AVP Stress Adaptation/Maladaptation Stress response, depression Maternal Corticosterone Regulates cerebral development in the fetus THE STRESS REACTIONTHE 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 THE CIRCADIAN TIMING SYSTEMTHE CIRCADIAN TIMING SYSTEM PVN Posterior Nucleus Anterior Nucleus SCN PVN Lateral preoptic Nucleus Median preoptic Nucleus Examples of human circadian rhythms Parathyroid Hormone Motor activity Core body temperature Urine volume Thyroid Stimulating Hormone Cortisol Time W 16 24816 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 Behavioral human circadian rhythmsBehavioral human circadian rhythms Rest - activity cycleSleep - Wake Cycle Circadian rhythms are flattened and disrupted in depressed patients Sleep ControlDepressed 20 40 60 80 100 69 12 15 18 21 24 369 Sleep PLASMA MELATONIN (pg/mL) PLASMA CORTISOL (ng/mL) Sleep 20 70 120 170 220 6912 15 18 21 24369 BODY TEMPERATURE (C) 7 9 111315171921237 9 1113531 37.2 37.0 36.8 36.6 36.4 36.2 36.0 Clock Time 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. Behavioral circadian studies in rodents DD: Free running conditions12/12 LD Cycle The Phase Response Curve Concept 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 Phase Response curve to induced hyperactivity Phase advances in the circadian activity rhythm during the second part of the no active phase of the animals activity cycle Phase delays during the late part of the active phase of the animals activity cycle Little or no effect at other phases Phase shifting effects of acute stress on the circadian clock : restraint stress 3-h periods of restraint stress at 8 different circadian times: The response The response of an of an organism organism to an acute to an acute stressor stressor varies as a varies as a function function of of the the time of time of day day of of stressor presentationstressor presentation The functioning The functioning of of the circadian the circadian system system is is affected affected by stress,by stress, and its response and its response to to stress stress is is a a function function of of the the time of time of day at day at which the stressor is appliedwhich the stressor is applied . . STRONG TIME-RELATED INTERACTIONS BETWEENSTRONG TIME-RELATED INTERACTIONS BETWEEN THE STRESS SYSTEMTHE STRESS SYSTEM AND THE CIRCADIAN SYSTEMAND THE CIRCADIAN SYSTEM 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 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 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 EFFECTS OF STRESS ON HUMAN SLEEPEFFECTS OF STRESS ON HUMAN SLEEP Sleep Sleep complaints/changes:complaints/changes: - - after disturbing after disturbing life life eventsevents - in - in chronic insomniac chronic insomniac patientspatients - in shift - in shift workers workers - in - in stress-related sleep stress-related sleep disordersdisorders - in - in depressiondepression INTERACTIONS BETWEENINTERACTIONS BETWEEN STRESS AND HUMAN SLEEPSTRESS AND HUMAN SLEEP Close temporal Close temporal link between link between HPA axisHPA axis activity and activity and sleepsleep Exogenous Exogenous administration of CRH, ACTH, Cortisol administration of CRH, ACTH, Cortisol can alter can alter sleep sleep architecturearchitecture Role Role of immune systemof immune system and its response and its response to stressto stress Sleep deprivationSleep deprivation , as a, as a stressor stressor , can, can induce induce longlong term term metabolic and metabolic and cognitive cognitive consequences consequences ofof glucocorticoid excessglucocorticoid excess 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 EFFECTS ON STRESS ON SLEEP: EFFECTS ON STRESS ON SLEEP: ANIMAL MODELSANIMAL MODELS Acute Acute restraint restraint stressstress Kyoto Kyoto Wistar Wistar ratsrats Prenatal Prenatal stress modelstress model EFFECTS OF ACUTE STRESS ON SLEEP IN RODENTSEFFECTS OF ACUTE STRESS ON SLEEP IN RODENTS Restraint Restraint stress (30 - 120 min)stress (30 - 120 min) Restorative sleepRestorative sleep : : PS SWS ( )PS SWS ( ) Circadian factorsCircadian factors : : time of time of day effectday effect altered corticosterone rhythm altered corticosterone rhythm MechanismsMechanisms : : CRH ActivationCRH Activation NorAdrNorAdr CLIP Activation 5HTCLIP Activation 5HT ProlactinProlactin Koehl Koehl et al, 2002et al, 2002 Wistar Wistar Kyoto Inbred RatsKyoto 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 WISTARWISTARWKYWKY 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 MODELTHE RESTRAINT PRENATAL STRESS MODEL PRENATAL STRESS AND BEHAVIORAL CHARACTERISATIONPRENATAL STRESS AND BEHAVIORAL CHARACTERISATION learning/memory disorders drugs of abuse vulnerability depressive-like behavior anxiety-like behavior Circadian rhythms ? ? Sleep - wake cycle ? ? Corticosterone Corticosterone circadian rhythm in adult male ratscircadian rhythm in adult male rats ) PRS Corticosterone (ng/ml) Time Effects Effects of PRS on of PRS on spontaneous Sleep-Wake spontaneous Sleep-Wake cyclecycle 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) Time (h) 48162024 1248162024 Correlation between sleep and Correlation between sleep and corticosteronecorticosterone 400 800 1200160020002400 Sleep fragmentation (dark phase) 200 250 300 350 400 450 500 r = 0.57 p=0.0224 TotalTotal corticosterone corticosterone (AUC)(AUC) in in response response to to restraint restraint stressstress CONT PRS 400 800 1200160020002400 % PS (total% PS (total recordi