Brain mechanisms that control sleep and waking Jerome Siegel By group 2

Electroencephalogram Developed by Hans Berger in Jena, Germany Records the electrical activity of the brain and provides objective measure of the state of the brain, and states of consciousness Berger’s work showed clear signs of sleep in 2 categories: REM and NREM Awake EEG characterized by low voltage (5-50 muV) and high frequency (20-40 Hz)

Stages of sleep (EEG cont) Sleep stage 1: EEG resembles waking state, transitional state Stage 2 and 3 characterized by sleep spindles Stage four has the highest amplitude and lowest frequencies Each cycle of Non-REM sleep is followed by a REM episode: 90 min and 5 sleep cycles in 8 hour sleep period

Stereotaxic instrument Developed by Victor Horsley and Robert Clark in London Head is fixed in standard orientation Atlas of brain with plates used to position the probe Permits probes to be inserted into the brain experimentally to manipulate deep structures

Cathode Ray Oscilloscope Necessary to explore the electrical activity of the brain at the single cell level Has virtually no inertia, can respond with millisecond, and submillisecond speed Permitted discovery of neural events at the cellular level that occur during waking and sleep

Encephalitis Lethargica During world wide influenza epidemic, “Spanish flu” Variant of the disease that cause sleep coma Discovered by Constantin von Economo using a stain selective to cell bodies revealed profound loss of cells in posterior hypothalamus and adjacent regions of mesencephalic reticular formation First evidence these structures were necessary in waking state Inability to sleep (insomnia?) – loss of cells in anterior hypothalamus and adjacent preoptic area of basal forebrain (these areas critical for ability to sleep)

Encephalitis Lethargica Areas important for waking -Posterior hypothalamus -Anterior reticular formation Areas important for sleep -Anterior hypothalamus -Preoptic area

Neural Structures and pathways for arousal Moruzzi and Magoun Electrically stimulated the mesencephalic reticular formation of cats when EEG signified a sleep-like state Upon stimulation onset rapid and dramatic change of EEG Destruction to the area stimulated, produced animals with sleep like behavior and EEG’s Due to the findings, the reticular formation became known as the ascending reticular activating system (ARAS)

Pathways for arousal Brachium Conjunctivum: a prominent fiber tract that goes through the pontine and mesencephalic brain stem Surrounding it are two nuclei (collectively known as the Peribrachial Nuclei) Pedunculopontine Tegmental Nucleus (PPT) Erodorsal Tegmental Nucleus (LDT) This nuclei contain acetylcholine-synthesizing neurons

Sagittal view of cholinergic pathways of rat

Dorsal and Ventral Pathways These two pathways mediate cortical arousal from activation to the peribrachial nuclei Dorsal Direct: peribrachial cells --> midline intralaminar nuclei of the thalamus- -> broad areas of cortex Glutamatergic projections from thalamus

Ventral Pathway Complex route, prior to thalamus, components course through ventral region of forebrain, or hypothalamus Hypothalamic cells of the nucleus release histamine which produces strong arousal on the cerebral cortex The neurotransmitter used to activate cortex are GLU, histamine, hypocretin and ACh

Neural control of NREM Sleep Siegel and colleagues Showed sleep inducing stimulation produced EEG slow wave while at the same time producing a firing pattern of cells in brain stem ARAS (decreased firing) Finding suggest that sleep inducing influence has its effect by inhibiting the neural activity of the ARAS

NREM and Basal forebrain area Involved in producing arousal Stimulation in cats produced EEG and behavioral signs of sleep Cholinergic cells that project to cortex mediate the basal forebrain producing arousal Sleep inducing effect of the basal forebrain is mediated by inhibitory effect of GABA on hypothalamic component or ARAS Without Basal Forebrain inhibitory influence, the histaminergic arousal system stays active which leags to inability to sleep (insomnia)

Neural control of REM Sleep 1953 Aserinsky and Kleitman Studied dream sleep During episodes of dream sleep there are Rapid Eye movements, and the EEG reflects that of an awake brain REM episodes occur in all mammalian species investigated and is sometimes seen in other vertebrates In addition to eye movements and EEG recordings of an awake-like state, there are autonomic changes as well: Irregular heart rate Increased blood pressure Increased pupil diameter

REM sleep Males show penile erection (sorry folks no picture available) Women show comparable signs of sexual arousal There are spike like transient waves from pons area, LGN, thalamus, and occipital cortex (referred to as PGO waves Electrodes close to the hippocampus show theta waves Non-autonomic changes of REM: Muscle tonus in straited skeletal muscle abolished

The fast activity EEG recordings from the cortex reflect a cognitively active brain; dream state The sympathetic arousal possibly prevents the dreams from being acted out However, it is unknown why there are theta waves from the hippocampal area The cholinergic peribrachial nuclei at the pontine-mesencephalic junction is activated during REM Since the dream state is emotionally charged, the ventral pathway which interacts with the hypothalamus and other limbic areas are activated during REM

When there is a lesion to the nucleus subcoeruleus of the dorsal pons, REM sleep paralysis becomes abolished Cats with lesions to the area become very agitated during REM sleep, as if acting out the dream REM onset and offset controlled circuits between the pons and medulla Also may be due to activity of cholinergic cells of the peribrachial nuclei and the mesopontine brain stem

Function of Sleep Approach most widely used to explore functions of sleep: sleep deprivation Evidence from studies suggest sleep serves at least two functions Keep the immune system functioning properly Facilitation of memory consolidation

Function of Sleep When fruit flies are prevented from resting, then allowed to rest, will show an increased amount of time in this quite state Suggests sleep is programmed homeostatic process that regulates time for sleep in insects and in humans It has proven difficult to selectively deprive subjects of slow-wave sleep and REM because REM only follows NREM slow-wave sleep

Function of Sleep In the late 1980’s Rechtschaffen and colleagues showed that depriving rats from sleep for 2-3 weeks would kill them They were also able to selectively deprive rats of REM sleep and it took 3-4 weeks for them to die (how nice!) Two of the most important changes that occurred during sleep deprivation of the rats were increased food intake (up %) while simultaneously showing significant weight loss

Function of Sleep The second change, which was said to be the ultimate cause of death, was bacterial infection The rats were highly susceptible to illness because sleep deprivation left their immune systems unable to fight incoming invaders (Everson and Toth 2000) There is some debate whether the cause of dysfunctional immune system was due to sleep dep. or stress.

Function of Sleep Effects of sleep deprivation are not as severe for humans After receiving vaccinations for hepatitis and influenza, human subjects who were deprived of sleep showed a reduction in the anti-bodies that protect against diseases. However, Siegel neglected to include how subjects were deprived from sleep and for how long.

Function of Sleep Other studies suggest sleep is important for memory consolidation Experiments have shown that subjects who are trained to perform a certain task and then allowed to sleep show better performance than subjects who are not permitted to sleep Hennevin and Colleagues found learning of subjects would show small daily improvements, and then on a particular day would show drastic improvement

Function of Sleep Hennevin and Colleagues also found performance was drastically improved immediately following REM sleep This data led Hennevin and Colleagues to propose that REM sleep is important for larger amounts of memory processing

Function of Sleep Another fascinating study was conducted by Stickgold and colleagues in 2000 that found subjects showed no improved performance unless they were allowed to sleep within 30 hours of training Stickgold and colleagues provided data to support the hypothesis that slow-wave sleep and REM sleep towards the morning are vital for the consolidation of memory

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