Sleep
PSB 5341
Spring, 2006
Introduction
• So far - wakefulness
• Rhythmic environment & behavior
• Sleep - general characteristics
– Recumbent posture
– Raised threshold to sensory stimulation
– Low level of motor output
– Unique feature - dreaming
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Electroencephalograms (EEGs)
Generation of very small electrical fields by
synaptic currents in pyramidal neurons
Cross-section of cortex:
Afferents release
glutamate
Open cation channels at
pyramidal cell dendrites
Only if thousands of
neurons contribute their
small voltage is the signal
large enough to see at the
scalp electrode - forest for
the trees
Generation of large EEG signals by synchronous
activity
Two mechanisms of synchronous rhythms
Top: Cues from a central clock or
pacemaker
Bottom: Distribute timing function
among members by mutual excitation
and inhibition of each other
Cortical rhythms depend on both
mechanisms, via thalamic maker input,
and collective cooperative interactions
among cortical neurons themselves.
Thalamic cells have a particular set of
voltage-gated ion channels to allow each
cell to generate rhythmic, self-sustaining
discharge patterns even in the absence of
external input to the cell.
To cortex via thalamocortical axons
A one-neuron oscillator
At times during sleep,
thalamic neurons fire in
rhythmic cadence that do
not reflect their input.
(a) A short stimulus pulse
applied & thalamic cell
responded with about 2-s
of rhythmic activity
(b) Two burst expanded in
time; each burst a cluster
of about 6 action
potentials
A two-neuron oscillator
One excitatory (E cell) neuron and
one inhibitory (I cell) synapse
upon each other.
As long as there is a constant
excitatory drive (not necessarily
rhythmic) onto the E cell, activity
will tend to trade back & forth
between the two neurons.
One activity cycle through this
simple two-cell network will
generate the firing pattern shown
in the dashed rectangle.
Rhythms in thalamus driving rhythms in cerebral cortex
Cortical rhythms: general purpose
1. Sleep - brain‟s way of
disconnecting the cortex from
sensory input
2. Awake brain often generates
bursts of synchronous neural
activity that elicit frequencies
around 30-80 Hz (sometimes
called gamma rhythms)
3. Momentary fast rhythms,
different parts of brain & cortex,
binds several components into a
common construction - percept,
complex act, etc
EEG of generalized epileptic seizure
(a) EEG electrodes in
typical array
(b) Seizure detected
across entire head,
begins abruptly,
synchronous
rhythms of about 3
Hz, ends after
about 12 seconds
(c) Causes: tumor,
trauma, metabolic,
infection, vascular
disease, genetic
predisposition
(e.g., mutated
sodium channels,
altered GAGA
synaptic inhibition)
EEG rhythms vary with particular states of behavior
EEG grouped based on
frequency range & named
a Greek letter:
Beta rhythms = > 14 Hz &
signal activated cortex
Alpha = 8-13 Hz, quiet,
waking
Theta = 4-7 Hz, during
some sleep stages
Delta = quite slow, < 4 Hz,
often large amplitude,
hallmark of deep sleep
Sleep in the bottlenose dolphin
R
Top: high-frequency activity on both
hemispheres during alert wakefullness
L
Middle: Large delta waves of deep
sleep only on right hemisphere with
activation on the left. R
L
Bottom: Activity patterns reverse
hemispheres R
L
Modern Era
• 1928, Aldolf Berger, German psychiatrist,
discovered human EEG, electroencephalogram,
state-dependent
• Loomis & Harvey, showed systematic changes in
EEG as subjects went to sleep
• Frederick Bremer, Belgian physiologist, similar
EEG sleep patterns in animals, research with cats
– Encephale isole, isolated brain
– Cerveau isole, isolated forebrain
– Motivated by concept of reflex arc (Pavlov,
Sherrington)
Brain Transections Reveal Sleep
Mechanisms
Cerveau
isole
Encephale
isole
Modern Era
• W. R. Hess, Swiss Nobel laureate, interests in
electrical stimulation subcortical mechanisms
mediating autonomic control (especially
hypothalamus)
– Electrically drive thalamocortical system at frequencies
of the EEG spindles & slow waves
– Induce behavioral & EEG signs of sleeping in
unanesthetized cats
– Opened the door that sleeping & waking may be active
processes, each with its own specific cellular &
metabolic mechanisms and function consequences
Modern era
• 1949 Giuseppe Moruzzi and Horace Magoun
– High-frequency stimulation of midbrain produced EEG
desynchronization & behavioral arousal
– Proposed reticular activating system (RAS); nonspecific,
nonsensory operates in parallel with ascending sensory pathways
– Lesions of midbrain RF, sparing ascending sensory pathways,
leads to NREM sleep state
• 1953 Eugene Aserinsky & Nathanial Kleitman
– Self-activate during sleep
– Regularly timed, spontaneous desynchronized EEG, REM, & acute
increased HR & breathing
– William Dement; these changes associated with dreaming
– Cycle of NREM (75-80%) & REM (20-25%) recurs with period
length of 90-100 min
Modern era
• Francois Michel & Michel Jouvet, 1959
– Control system for REM sleep located in pons
– Pons sources of EEG activation & REMs
– Pontine signals also responsible for muscle inhibition
via reticular formation to spinal cord
– Ponto-geniculo-occipital (PGO) waves or bursts of
synchronous activity; EEG, REM, spinal cord damp
sensory input (via pre-synaptic inhibition) and motor
output (via post-synaptic output, glycine)
Brainstem RF: contains neuronal groups involved in
behavioral state regulation
• Two principles
– Specific afferent inputs & organized outputs
– Composed of small groups of neurons that send widely
branching axons to distal parts of brain, modulate brain
function
• Cell groups
– NE neurons (designated A1-A7), locus coeruleus
(major group, A4 & A6); one component projects
caudally to sensory regions of brain stem & spinal cord.
2nd group projects to cerebellar cortex, dorsal
thalamus, cerebral cortex
Brainstem RF
• 5-HT neurons (B1-B9) brainstem raphe; from
caudal medulla to midbrain, midline of brainstem
RF, dorsal & median raphe (largest group, B8 &
B9), project rostrally to entire forebrain
• ACh neurons, 2 important sets
– 2 pontine nuclei: laterodorsal tegmental nucleus &
pedunculopontine nucleus; these ACh neurons project
to brainstem RF, hypothalamus, thalamus, basal
forebrain
– Medial septum, n of diagonal band, substantia
innominata; these ACh neurons project to limbic
forebrain, including hippocampus & neocortex
Sensorimotor versus Modulatory neurons
• Sensorimotor • Modulatory
– Large diameter (50-75 – Small diameter (10-25
um in diameter um in diameter)
– Fire at high rates (50- – Fire wider spikes at
500 Hz) in clusters or slower rates (1-10 Hz);
bursts pacemaker, metronome
– Fast conducting (100 pattern
m/s) – Slow conducting (1
m/s)
Some basic principles
• Diffuse modulatory neurons are most critical to the control
of sleeping and waking
• Brainstem NE and 5-HT fire during waking & enhance the
awake state; some Ach neurons enhance critical REM
events, and other cholinergic neurons are active during
waking
• Diffuse modulatory systems control rhythmic behaviors of
the thalamus, which in turn controls many EEG cortical
rhythms; slow, sleep-related rhythms of the thalamus block
flow of sensory information to cortex
• Sleep also involves activity in descending branches of the
diffuse modulatory systems, such as inhibition of motor
neurons during dreaming.
Norepinephrine System
Locus coeruleus = Latin for
„blue spot‟because of the
pigment in its cells
Axons fan out to innervate just
about every part of brain: entire
cerebral cortex, thalamus,
hypothalamus, cerebellum,
midbrain, spinal cord
1 neuron can make 250,000
synapses & one have on axon
branch in the cerebral cortex
and another in the cerebellar
cortex
Involved in regulation of
attention, arousal, sleep-wake
cycles
Activated best by new,
unexpected stimuli
Make cortex more responsive to
salient sensory stimuli
Serotonin system
Clustered within 9 raphe
nuclei.
Raphe means „ridge‟ or
„seam‟in Greek. Lie to
either side of midline
Those more caudal
innervate spinal cord,
modulate pain
Those more rostral
innervate innervate most
of the brain like LC NE
neurons
Like LC neurons, they
fire more rapidly during
wakefulness, most quiet
during sleep
Acetylcholine system
Two diffuse modulatory systems in
brain
1. Basal forebrain complex -
medial septal complex & Basal
nucleus of Meynert
2. Pontomesencephalotegmental
complex, project to thalamus
and parts of forebrain. Works
together with the NE and 5-HT
systems to regulate excitability
of sensory relay nuclei
Wakefulness & Ascending Reticular Activating
System
• Neurons increase their firing in anticipation
of awakening & during various forms of
arousal
– LC (NE); Raphe (5-HT); Brainstem & basal
forebrain (ACh); & midbrain histamine neurons
synapse directly on entire thalamus, cortex,
depolarize & increase excitability
Falling asleep & non-REM sleep
General decrease in firing rate of most brainstem
modulatory neurons (NE, 5-HT, ACh)
Most neurons of basal forebrain promote
alertness/arousal, a subset of ACh neurons
increase their firing rate with onset of non-
REM sleep and are silent during wakefulness
PET (positron emission tomography) images of the waking and
sleeping brain
Left: REM-Wake, 3 horizontal sections of human brain. Color represents activity between REM
sleep and waking. Black=no difference; yellow/red=more activity; blue/purple=less activity.
Same - Primary visual cortex, REM greater in extrastriate cortex & limbic areas; Wake greater in
frontal lobes
Right: REM sleep compared to non-REM sleep (SWS). REM less active in primary visual cortex,
but extrastriate cortex more active. During REM, there is an explosion of extrastriate activity,
possibly during dreaming, but no comparable activity in primary visual cortex. This suggest that
extrastriate activation is internally generated. The emotional component to dreams may come from
increased limbic activation.
Control of REM (as other brain states) comes from diffuse
modulatory systems in the brainstem core, mostly pons
Firing rate of 2 major systems (LC-NE; raphe-5-HT) in upper brainstem decrease to almost nothing
at onset of REM
REM-on cells are cholinergic neurons in the pons, and they increase their firing rate just before onset
of REM (red line). Some evidence suggest that these cholinergic neurons induce REM sleep.
REM-off cells are noradrenergic & serotonergic neurons of the locus coeruleus and raphe nuclei,
respectively, and their firing rates increase just before the end of REM (blue line)
Hypothalamus
• Lesions of posterior hypothalamus produced
sleep/hypersomnolence; lesions to anterior-
preoptic reduced sleep (insomnia)
• During NREM, VLPO, ventrolateral preoptic area,
contains GABA & galanin neurons that inhibit
posterior hypothalamus, particularly
tuberomammillary nucleus (TMN) containing
histamine-containing, wake promoting neurons
that project to thalamus and cortex.
• Circuit for monosynaptic switch for the alternation
between sleep & wakefulness.
• Orexin neurons in lateral hypothalamus also
important
Brains of
human
narcoleptics
have about
10% or less of
hypocretin
neurons.
Narcolepsy is a bizarre and disabling disturbance of sleeping & waking. Excessive daytime
sleepiness can be severe and often leads to unwanted “sleep attacks.” EEG monitoring suggests that
narcoleptics go directly from waking into REM sleep without normal period of non-REM first. Also
occurs in goats, donkeys, ponies, & more than a dozen breeds of dogs. Canine narcolepsy caused by a
mutation of the gene for a hypocretin/orexin receptor. Orexin neurons project widely in brain &
excite ACh, NE, 5-HT, DA, and histaminergic modulatory systems.
Sleep-promoting factors
• Muramyl dipeptide: Sleepiness associated with infectious
diseases, flu & cold. Relationship between immune
response & sleep. Interleukin-1 is a peptide that
stimulates immune system & synthesized in brain, glia,
macrophages
• Adenosine: used by all cells (DNA, RNA, ATP);
antagonists of adenosine receptors like caffeine keep
people awake. Adenosine administration promotes sleep.
Longer awake, the more adenosine. Adenosine inhibits
Ach, NE, 5-HT
• Melatonin: Produced by pineal gland. Levels rise in
evening, peak in early morning, fall to baseline at
awakening.