Normal Sleep: Neurobiological Mechanisms

Normal Sleep: Neurobiological Mechanisms

Objectives Why sleep? What makes us sleep? How is normal sleep achieved? When do we sleep?

why do we need sleep? Biologic and Homeostatic Drives eat to satisfy hunger, and provide nutrients sleep to feel rested, and provide.?

Totals sleep time is inversely proportional to body size 18hrs 14hrs 12hrs 10hrs 7hrs Siegel J, Scientific American, Nov 2003

Sleep time in mammals Seigel J, Nature 2005

Normal sleep Architecture Sleep entered through NREM sleep Sleep cycles: NREM and REM sleep alternate thru the night in the cyclic fashion First Cycle average length 70-100 minutes Second and later cycle average length 90-120 minutes Stage 1 2-5% Stage 2 45-55% SWS 15-20% REM 20-25%

Broad Sense: Why sleep? Sleep (NREM and REM) is present in ancestral organisms even fruit flies and has some biologic advantage. Unresolved issues: Sleep in birds and mammals may have evolved independently. Developmentally sleep and REM sleep in particular are often expressed at a high level before the emergence of NREM and adult patterns of wake/sleep transition. Sleep is embedded in a circadian rhythm.

Current theories Primary Remodel synaptic plasticity induced by wakefulness. Restore brain energy stores. Secondary Consolidation of certain kinds of learning Endocrine functions Restore body systems

Why we need NREM? Reverse toxic effects of Wakefulness ROS are found in hypothalamus but not on neo-cortex Sleep enables decline in ROS production and facilitates replacement of cellular components of neurons and ganglia Protein synthesis and neurogeneration SWS is associated with higher rates of protein synthesis throughout the brain Memory consolidation: concepual Nakanishi et al Eur J Neurosci 1997 Ramp P, Smith CT Physiol Behav 1990

Why we need REM? What is REM? State of high brain metabolic and neuronal activity rates Reduced muscle tone Diminished thermoregulation Reinoso-Suarez F, Sleep Medicine Reviews, 2001

Why we need REM? REM amount/tst correlates with immaturity at birth Giraffe & guinea pigs (precious) versus the platypus (atricial) Monoamine replenishment Transport mechanisms & receptors Prime for awake state Memory Complex Motor performance Siegel J, PLoS biol, 2005 Madhu K, Metabolism Clinical and Experimental, 2006

REM and Developmental Plasticity Development (MD is monoocular light deprivation) MD w/ REM deprivation MD Non-REM deprived Cell size nonpatched eye Cell size from patched segment 233.92 206.21* 274.61 250.36 Endogenous activity that tend to prevent abnormal brain connections Prevents programmed cell death Eliminating superfluous brain matter Shaffery JP, et al Sleep 1998

How or what makes us sleep? Starting with neurotransmitters and wakefulness

Wake Neurostransmitters Histamine (TMN) Determinant of wakefulness & consciousness Involved in forebrain arousals Inactive in REM Adrenergic (Various) Regulate awake muscle tone/activity Inactive in REM Dopamine (Ventral tegmentum of Midbrain) Serotonin (LC and midbrain raphe) Highest in Wake/ Lowest in REM Regulate muscle tone in REM (inhibits eye movements of REM and muscle twitch generation) Hypocretin (perifornical region of lateral Hypothalamus) Drive the other arousal NT s Saper Trend Neurosci 2001

Reticular Activating System (RAS) dorsal and ventral pathways Acetylcholine Basal forebrain LDT/PPT Thalamic relay (+) Reticular nucleus of the Thalamus (-) Histamine Broad activation Specific inhibition of VLPO sleep Aminergic system Saper Trend Neurosci 2001

Orexin: Awake & Sleep PPT/LDT Periformical region of the hypothalamus Activates histaminergic, serotonergic, and cholinergic systems Orexinergic

Awake & Sleep NT s Serotonin Adrenergic Histamine Orexinergic GABA

Sleep transitions from Wake NT s Serotonin Adrenergic Histamine Orexinergic GABA

Hypothalamic VLPO control: Flip-Flop GABA Sleep-on Reticular Activating System (RAS) Sleep-off Kryger, Principles of Sleep Medicine, 2006 Saper, Trends in Neuroscience, 2001

Reticular Activating System VLPO NE 5HT TMN LC/DR Histamine PPT LDT Awake Lu et al., 2002, 2006

GABA Sleep-on VLPO TMN LC/DR GABA nrem REM (VLPO-ex) PPT LDT Lu et al., 2002, 2006

ORX Stabilizer FLIP-FLOP Prevents intermediate states VLPO Sleep Arousal NE 5HT TMN LC/DR GABA Histamine nrem REM (VLPO-ex) PPT LPT Lu et al., 2002, 2006 Saper et al., 2006 Lin et al., 1999 Awake

Flip-flop Switch nrem REM VLPO TMN NE, 5HT Histamine OREXIN Sleep Wake

Ventrolateral peri-aqueductal grey matter VLPO m e a W ) d e c d t o s e Lu et al., 2006 LD/PPT Lateral Pontine Tegmentum

Peri-aqueductal grey matter - Pons 5-HT hypocretin REM-off + vlpag + Lateral Pontine Tegmentum Nor-adrenergic REM-on Timing of REM Acetylcholine LD/PPT + Sub-Laterodorsal Nucleus Lateral Pontine Tegmentum Lu J, Sherma D, et al Nature 2006

Sudden, strong emotions RAS 5-HT, NA, Hist Excitation Inhibition Limbic System Hypocretin REM-on Norepinephrine, 5-HT Glutamate*, Glycine** *magnocellular nucleus of medulla **Lateral reticulospinal tract * Adapted from Siegel J, 2006 Motor neurons Postural muscles

When do we sleep?

Cues for sleep: Circadian zeitgebers Light Food Social Exercise Indirect Melatonin Adenosine

Hormonal rhythm control Light: 1. Strong phase shifter 2. MLT peak is proportional to light portion 24h/cycle 3. Pulse of light at peak MLT levels produces rapid suppression Moore R., Behavioral Brain Research 1996

LP Orexin PVH Steroids VLPO Sleep Limbic System Visceral Cortex Temp Grehlin apetite Sympathetic system via superior cervical ganglion Pineal Leptin satiety Cho T, et al., 2003 Saper C, 2005

Meerlo P., et al,. Review Stress, 2005 Merrlo, et al., 1997 Uncomfortable social interactions dampen circadian rhythms Quality of sleep is principally affected Stress neuroendocrine signals ( stress ) do not have a major effect on circadian rhythm AVP may delay clock

Sex Differences Normal Menstrual Cycle Progesterone = soporific Subjective sleepiness in luteal phase No significant differences in sleep between follicular and luteal phases: EEG Total sleep time Sleep onset REM and non-rem time Psychiatry Clin Neurosci. 1999 Apr;53(2):207

LH and sleep LH surge during sleep is the harbinger of puberty in women. In adult life LH is not closely associated with sleep states.

Growth Hormone and Sleep NREM sleep and GH surges

ACTH/Cortisol and Sleep In contrast to GH, more driven by circadian than sleep CRF/ACTH and then Cortisol increase are associated with a rising temperature profile and alerting process at the end of the major sleep cycle. Inverse relationship between delta waves and cortisol

Prolactin and Sleep Increases in prolactin with sleep onset SWS even when there is a change in circadian rhythm The mechanism may be a reduction in dopamine, which usually inhibits prolactin Increased SWS with prolactinomas Prolactin elevations increase REM sleep and reductions reduce REM sleep.

Summary Sleep is necessary for brain cell structure health & wellness N-REM is homeostatic for brain metabolism REM arranges neurophysiologic state Specific opposing neurotrasmitters action Awake/sleep is regulated by stable flip-flop mechanism Circadian control mediated by light>melatonin Somatic, limbic cues are strong regulators

References Siegel J, Clues to the functions of mammalian sleep, NATURE, vol437, 2005 Siegel J, Why we sleep SCIENTIFIC AMERICAN, November 2003 Meerlo P, et al., The Effects of Social and Other Stressors on the Expression of Circadian Rhythms, STRESS, 2002 Vol.5 Siegel J, The Neurotransmitters of Sleep, J CLIN PSYCHIATRY, 2004;65 Siegel J, The stuff dreams are made of: anatomical substrates of REM sleep, NATURE NEUROSCIENCE, VOLUME 9, # 6, JUNE 2006 Crowley S, et al., Combinations of Bright Light, Scheduled Dark, Sunglasses, and Melatonin to Facilitate Circadian Entrainment to Night Shift Work, JOURNAL OF BIOLOGICAL RHYTHMS, Vol.18 No.6, December 2003 Fuller P., Neurobiology of the Sleep-Wake Cycle, JOURNAL OF BIOLOGICAL RHYTHMS, Vol 21, 2006 Deboer T, Sleep states alter activity of suprachiasmatic nucleus neurons, NATURE NEUROSCIENCES, Vol 6;10: 1086 Siegel J, The stuff dreams are made of: anatomical substrates of REM sleep, NATURE NEUROSCIENCE VOLUME 9, NUMBER 6, JUNE 2006 Duffy F, Phase-Shifting human circardian rhythms: influence of sleep timing, social contact and light exposure JOURNAL OF PHYSIOLOGY 1996

References Reinoso-Suarez F, et al., Brain structures and mechanisms involved in the generation of REM sleep, SLEEP MEDICINE REVIEWS, Vol.5, No.1, pp63-77, 2001 Shaffery P, et al., REM sleep deprivation in monocularly occluded kittens the size cells in LGN monocular segment, SLEEP, 1998 Dec 15; 21(8): 837-45 Saper C, et al., Homeostatic, Circadian, and Emotional Regulation of Sleep, THE JOURNAL OF COMPARATIVE NEUROLOGY, 493:92-98 (2005) Moore Y.R, Neural control of the pineal GLAND, BEHAVIORAL BRAIN RESEARCH 73 (1996) 125-130 Saper C, et al., The sleep switch: hypothalamic control of sleep and wakefulness, TRENDS IN NEUROSCIENCES Vol.24No.12, December 2001 Siegel J, Functional Implications of Sleep Development, PLOS BIOLOGY, May 2005,Volume 3, Issue 5, e178 Kalia M, Neurobiology of sleep, METABOLISM CLINICAL AND EXPERIMENTAL 55 (Suppl 2) (2006) S2-S6 Strecker R, et al., Adenosinergic modulation of basal forebrain and preoptic/anterior hypothalamic neuronal activity in the control of behavioral state, BEHAVIOURAL BRAIN RESEARCH 115 (2002) 183-204 Li Y, et al., Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron-A Potential Mechanism for Orchestrating the Hypothalamic Arousal System, NEURON,Vol.36, 1169-1181, December 19, 2002

References Li Y, et al., Hypocretin/Orexin Excites Hypocretin Neurons via a Local Glutamate Neuron-A Potential Mechanism for Orchestrating the Hypothalamic Arousal System, NEURON,Vol.36, 1169-1181, December 19, 2002 Chou T, et al., Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms, THE JOURNAL OF NEUROSCIENCE, november19, 2003#23(33): 10691-10702 Germain A, et al., Neurobiology of Non-REM Sleep in Depression: Further Evidence for Hypofrontality and Thalamic Dysregulation, AM J PSYCHIATRY 161:10, October 2004 Chou T, et al., Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms, THE JOURNAL OF NEUROSCIENCE, November 19,2003 *23(33:10691-10702 Teclemariam-Mesbah R, Anatomical Demonstration of the Suprachiasmatic-Pineal Pathway, THE JOURNAL OF COMPARATIVE NEUROLOGY 406:171-182(1999) Shaffery J, et al., REM Sleep Deprivation in Monocularly Occluded Kittens Reduces the Size of Cells in LGN Monocular Segment, SLEEP, Vol.21, No.8, 1998 Van den pol A, et al., Presynaptic and Postsynaptic Action and Modulation of Neuroendocrine Neurons by a New Hypothalamic Peptide, Hypocretin/Orexin, THE JOURNAL OF NEUROSCIENCE, October 1, 1998,18(19): 7962-797

References Chou T, et al., Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms, THE JOURNAL OF NEUROSCIENCE, november19, 2003#23(33): 10691-10702 Germain A, et al., Neurobiology of Non-REM Sleep in Depression: Further Evidence for Hypofrontality and Thalamic Dysregulation, AM J PSYCHIATRY 161:10, October 2004 Chou T, et al., Critical Role of Dorsomedial Hypothalamic Nucleus in a Wide Range of Behavioral Circadian Rhythms, THE JOURNAL OF NEUROSCIENCE, November 19,2003 *23(33:10691-10702 Mieda M, et al., The dorsomedial hypothalamic nucleus as a putative food-entrainable circadian pacemaker, Vol 103:32