The Neural Control of Behavioral State

Transcription

1 The Neural Control of Behavioral State Learning objectives: Introduction - Behavioral State; why do we sleep? A Clinical Case - The Sleeping Beauty of Oak Park. EEG - A Neural Signature of Behavioral State. Behavioral State is Rhythmic - Homeostatic vs Circadian Drives. Neurobiological insights from lesion-induced loss of function - Bremer, Moruzzi and Magoun. The Ascending Reticular Activating System. More insights from lesion-induced loss of function - Nauta. The hypothalamus in regulation of behavioral state; identified circuits. Brainstem Arousal Circuits. REM sleep and dreaming. Narcolepsy - Loss of integrated action in behavioral state regulation.

2 Behavioral State: An Introduction Our existences is characterized by daily cycles of activity and rest, more commonly known as the sleep-wake cycle. Consciousness is associated with waking. Consciousness is defined as an awareness of self and surround. Consciousness is governed by content and arousal. Content is the sum of cognitive and mental functions. Any lesion that interferes with cognitive function reduces the conscious state irrespective of the state of arousal. Arousal relates to the level of alertness. Cognitive function is heavily dependent upon arousal state, but arousal does not guarantee effective cognition. Localization of function and distributed processing determine behavioral state. The importance of behavioral state in adaptive behavior is apparent in the distributed redundant circuitry that administers its function.

3 Stages of Consciousness 1. All stimuli blocked from reaching consciousness; deep anesthesia or brain dead. 2. Dreaming during sleep or anesthesia; stimuli may influence dream content. 3. Deficient will to act. 4. Inability to respond regardless of total awareness. 5. Commands lead to purposeful movement. A = conscious state. B = awareness & comprehension of stimulus. C = will and intention to respond. D = ability to respond. Sensory input results in purposeful behavioral output only when all aspects of conscious information processing and motor readiness are functional. Langsjo et al., 2012

4 The Human Condition The Sleep Wake Cycle (SWC) Consciousness alternates with periods of rest. Cycles of activity and sleep are biologically determined. Sensory input from the eyes synchronizes the SWC with the light-dark cycle.

5 The Functions of Sleep REM sleep begins in the third trimester of gestation and alternates with periods of inactivity. It is postulated that this oscillatory activity is essential to the programmed gene expression that generate critical periods of development. Sleep provides a period of rest that allows a series of restorative actions both in the brain and other systems. Sleep is essential to life. Sleep plays a role in the consolidation of memories. Sleep is essential for mental health. Hobson (2009) posits that sleep prepares the mind for the conscious state.

6 Restorative Properties of Sleep Sleep great nature s second course, Chief nourisher in life s feast. (Macbeth, Act II) Adenosine-5 -triphosphate (ATP) is used in energy-consuming cellular processes. Thus, ATP levels are a measure of energy consumption. ATP levels surge during the onset of sleep in areas of the brain active during waking. The surge in ATP is tightly coupled to non-rem sleep, when neuronal activity and energy consumption are low. Sleep deprivation prevents the NREMassociated surge in ATP. 87% of brain energy consumption is correlated with neuronal firing rate. Dworak et al., 2010 The brain (2% of body mass) accounts for 20% of oxygen & glucose used by the entire organism.

7 Sleep and Mortality Risk Yoked rats were instrumented to record EEG and placed on a disk over water in identical chambers. When EEG detected sleep stages in the deprived rat the disk rotated. Non-deprived rats could sleep when the deprived rat was awake. Food and water were freely available for both rats and the environment was controlled. Deprived rats died within weeks from a variety of disorders. Animals in these experiments lost weight in spite of eating the same amount as controls and also lost thermoregulatory capacity. Rechtschaffen et al., 1983 Effective human cognition dependents upon effective temperature control. Thus, consciousness and cognition are closely tied to effective thermoregulation.

8 Sleep and Memory Metha, M. R., Nature Neuroscience 10: 13-15, 2007 Memory consolidation Electrophysiological studies demonstrate that the content of the memories is replayed in the hippocampus during sleep (McNaughton et al, 2000).

9 Effects of Sleep Deprivation on Performance PVT Measure of Sustained attention David Dinges University of Pennsylvania The number of hours of sleep one gets each night determines how alert the individual will be while awake. Chronic sleep deprivation impairs performance. Similarly, the ability to learn new tasks is directly correlated with habitual nightly sleep duration. Van Dongen et al., 2003 Psychomotor vigilance tasks (PVT) were measured for individuals deprived of sleep for differing periods over a two week period. Restriction to 4, 6 and 8 hours of sleep per night resulted in increasing errors over the two week period. The level of errors produced in the 4 and 6 hour groups was shown to be equivalent to that of hours of total sleep deprivation.

10 Sleep Deprivation and Attention Lim et al., 2010 Activation of brain during attention tasks in rested wakefulness (RW) and following 24 hours sleep deprivation (SD).

11 The Case of Sara S. Sara S. is better known as the sleeping beauty of Oak Park (a suburb of Chicago). In 1926, when she was 12 years old, she developed influenza at the end of a pandemic that swept the globe from 1916 to Following recovery from the respiratory effects of the influenza, she gradually became unresponsive and went into a coma from which she never recovered, although she lived for another 15 years. This was a common course for the sleeping sickness, which was subsequently shown to result from viral encephalitis. The clinical course of this disease was described by Baron Constatin von Economo and is now widely known as von Enconomo s encephalitis lethargica. Remarkably, the disease disappeared following 1926 and there have been no further documented occurrences. An autopsy following Sara s death revealed a lesion including posterior hypothalamus and rostral reticular formation that was similar in location to others who suffered from this disease

12 Encephalitis Lethargica Baron Constantine von Economo! Encephalitis lethargica - persistent coma - characterized by lesions in posterior hypothalamus and rostral brainstem. Other Symptoms: Fever, headache, double vision, delayed mental responses and - not surprisingly given its name - lethargy. Encephalitis lethargica is a disease characterized by high fever, headache, double vision, delayed physical and mental response, and lethargy. In acute cases, patients may enter coma. Patients may also experience abnormal eye movements, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis. The cause of encephalitis lethargica is unknown. Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world, but no recurrence of the epidemic has since been reported. Recent studies of patients exhibits similar symptoms has linked the disease autoimmune attack after Streptococcal infection.

13 Encephalitis Lethargica Baron Constantine von Economo! Encephalitis lethargica - persistent coma - is characterized by lesions inposterior hypothalamus and rostral brainstem. Autopsy & imaging of individuals exhibiting symptoms reveal lesions impinging upon posterior hypothalamus & the reticular core of brainstem.

14 Hans Berger and the EEG The Electroencephalogram Hans Berger Berger, H. Über das Elektroenkephalogram des Menschen. Archiv Psychiatrie Nervenkrankheiten, 1929, 87: EEG - an objective measure of brain function, particularly behavioral state.

15 A Neural Signature of Behavioral State The Electroencephalogram Electroencephalogram (EEG) is recorded from surface electrodes on the scalp and provides information on the neural activity of the cerebral cortex.

16 The Electroencephalogram Waking: EEG: Low voltage, fast frequency. The EEG reflects an activation of cerebral cortex via thalamus that results from interaction with the environment. Non-REM Sleep: EEG: High voltage, low frequency. The EEG reflects a decrease in cortical activation, but the individual is susceptible to sensory input and arousal. REM Sleep: EEG: Low voltage, fast frequency; very similar to that of waking. The EEG reflects an active cortex, with an inhibition of sensory input & motor output. Nathaniel Kleitman! The Waking and REM EEGs are Very Similar

17 The Electroencephalogram REM NREM Approximate 90 minute cycles of NREM/REM Sleep Episodes of REM & NREM Sleep Alternate through the Night

18 The Behavioral State Profile Electromyogram Electroencephalogram Electrooculogram

19 Circadian versus Homeostatic Regulation of Sleep-Wake Cycles (S = Homeostatic drive, C = Circadian drive) (MODIFIED FROM DAAN S, ET AL, AM J PHYSIOL 246: R161-R183, 1984) Homeostatic Drive & Circadian Drive combine to generate a sleep-wake cycle.

20 Circadian Drive Opposes Homeostatic Drive Homeostatic drive for sleep A sleep substance, S, accumulates progressively during the waking period. The higher the concentration of S the greater the drive for sleep. Sleep Onset Circadian drive for arousal A biological clock in the hypothalamus has a period approximating a day. Increasing neural activity in the clock promotes arousal through its neural network. Homeostatic Drive for Sleep Prevails when Clock Activity Decreases

21 The Neural Control of Behavioral State Beyond the Hypothalamus Insights from lesion-induced loss of function. The experiments of Bremer. The experiments of Moruzzi and Magoun. Frederic Bremer! Giuseppe Moruzzi and H.W. Magoun

22 Ascending Pathways and Consciousness Normal sensory input with cortical activation = Cerebral Cortex Thalamus Midbrain Pons-Medulla * ** * Sensory Input

23 Bremer s Experiment - Encephale Isole Input from Spinal Cord Eliminated by Transection at the Spinomedullary Junction = Cerebral Cortex Thalamus Midbrain Pons-Medulla * ** Transection * Sensory Input

24 Bremer s Experiment - Cerveau Isole Brain Transection at Midbrain = Cerebral Cortex Transection Thalamus Midbrain Pons-Medulla * * * Sensory Input

25 Moruzzi and Magoun Lesions of the Reticular Core Cause Cerebral Cortex Lesion Importantly, the lesion spared surrounding sensory pathways.

26 = Ascending reticular activating core Moruzzi and Magoun Stimulation of the Brainstem Reticular Core Cerebral Cortex Stimulation!

27 The Reticular Formation Neural Pathways Supporting Arousal The locus coeruleus (noradrenergic) and raphe nuclei (serotoninergic) reduce activity during SWS and are silent during REM sleep.

28 Distributed Control of Behavioral State Behavioral Analysis after Hypothalamic Lesions Nauta s Sleep Centers OB T RF MRI of Rat Brain in Sagittal Section OB Walle Nauta Lesions of the rostral or caudal hypothalamus produce insomnia or coma, respectively. insomnia H = Hypothalamus T = Thalamus OB = Olfactory bulb RF = Reticular formation = Lesion Placement Nauta postulated hypothalamic Sleep Centers based upon lesion-induced influences upon arousal. H T RF somnolence

29 Hypothalamic Regulation of Behavioral State Four Hypothalamic Cell groups Influence sleep-wake cycles = SCN GABA = VLPO GABA = Perifornical Hypocretin = TM Histamine Suprachiasmatic Nuclei: Circadian pacemaker; genetically determined oscillator, promotes arousal. Ventrolateral Preoptic Nuclei: GABAergic cell groups in rostral hypothalamus that promote sleep. Perifornical Nuclei: Hypocretin containing neurons in caudal hypothalamus that promote arousal. Tuberomammilary Nuclei: Histaminergic neurons in caudal hypothalamus that promote arousal. Identification and characterization of the cell groups in the contemporary literature validate the concept of sleep centers put forward by Walle Nauta in the 1950s.

30 Hypothalamic Regulation of Behavioral State Four Hypothalamic Cell groups Influence sleep-wake cycles Hypocretin Histamine = SCN GABA = VLPO GABA = Perifornical Hypocretin = TM Histamine The Hypocretin and Tuberomammillary Nuclei Promote Arousal through Diffuse Projections to the Cortical Mantle. Hypocretin neurons also innervate brainstem nuclei that promote arousal.

31 Hypothalamic Regulation of Behavioral State Four Hypothalamic Cell groups Influence sleep-wake cycles Hypocretin Histamine = SCN GABA = VLPO GABA = Perifornical Hypocretin = TM Histamine VLPO GABAergic neurons are activated at the onset of sleep (Saper et al) and inhibit caudal hypothalamic cell groups (perifornical and tuberomammillary) known to promote arousal.

32 VLPO Inhibition of the Ascending Arousal System Saper et al, Nature 437: , 2005 The VLPO Becomes Active at the Onset of Sleep.

33 HOMEOSTATIC DRIVE What is S and where does it act? Ach Adenosine is thought to be the sleep substance that accumulates during wakefulness. It is postulated to inhibit a cholinergic (Ach) arousal center in the basal forebrain.

34 Hypothalamic Regulation of Behavioral State Four Hypothalamic Cell groups Influence sleep-wake cycles Hypocretin Histamine = VLPO GABA = VLPO GABA = Perifornical Hypocretin = TM Histamine Homeostatic drive for sleep acts through VLPO.

35 Hypothalamus & Sleep Onset, Homeostatic drive, and the Onset of Sleep (Urade, 2011) L-PGDS = lipocalin-type PGD synthase

36 Basic Mechanisms of Waking Activated, Desynchronized Cortical State These cell groups stimulate arousal: Basal forebrain: Nucleus Basalis. Thalamus: Intralaminar Nuclei. Hypothalamus: Perifornial and Tuberomammillary Nuclei. Brainstem: Locus coeruleus and sertoninergic cell groups. Saper et al, Nature 437: , 2005 Brainstem cholinergic cell groups (LDT & PPT) facilitate thalamocortical transmission. Arousal groups (red) activate the cortex to facilitate processing of information from the thalamus.

37 Narcolepsy: A Failure of Integration Jerome Segal Hypocretin Neurons.. Project densely to arousal centers such as the locus coeruleus. Degenerate in hypothalamus of narcoleptics. The Doberman Narcoleptic dog model was shown to have a deletion in the hypocretin receptor. About Narcolepsy.. Excess daytime sleepiness. Sleep paralysis. Hypnagogic hallucinations. Cataplexy.

38 A Neural Basis for Narcolepsy Malfunction of Behavioral State Circuits (Saper et al, Nature 437: , 2005 It has long been postulated that brainstem cell groups constitute a REM Switch that generates REM sleep. The identity the cell groups that constitute the switch is debated. However, strong evidence supports the conclusion that hypocretin stabilizes the switch. Absence of hypocretin, or mutation of its receptors, contributes to switch instability and narcolepsy.

39 A FEW GOOD PARTING WORDS