NEURAL MECHANISMS OF SLEEP (p.1) – (Rev. 3/21/07)
1. Revisitation of Bremer’s 1936 “Isolated Brain” Studies
Transected the brain:
a. Cut between the medulla and the spinal cord (“encephale isole”)
Note: recall that in the 1930s the “passive” brain being driven into
W was the major hypothesis
By cutting the CNS at this level, still have 4 of the 5 major senses still
coming into the brain via cranial nerves
so…Cat’s brain should still show what re. Sleep (REM&SWS) & Wake?
And, what did it show?
b. Cut between the inferior and superior colliculi (“cerveau isole”)
By cutting the CNS at this level, would only have 2 of the 5 senses still
coming into the brain via cranial nerves
so…Cat’s brain should show what re. Sleep & Wake?
And, what did it show?...
What was Bremer’s (incorrect) interpretation of these data?
That indeed the brain was “passive”, was driven into W by incoming
sensory stimulation, w/o which brain lapses into sleep…
But what if there was another explanation?…..
What if there were a brain center just posterior to cut made in midbrain
and just anterior to cut made in hindbrain, and what if that center
generated wakefulness (and REM)?
2. Reticular Activating System Æ W
This structures generates wakefulness, alerting
Discovered in late 1940s by UCLA researchers Moruzzi & Magoun
Core of diffuse neurons lying midbrain+hindbrain
Receives information from many incoming sensory pathways
Sends axons to many areas of forebrain (incl. thalamus, basal ganglia, and
basal forebrain)
If stimulate RAS while S is asleep Æ?
NEURAL MECHANISMS OF SLEEP (p.2)
2. Reticular Activating System (cont.)
If stimulate RAS while S is awake Æ?
If lesion the RAS Æ?
What happens if you cut all the incoming sensory signals to the RAS but leave
the RAS itself intact?... Æ
Thus, sleep and wake are active processes that are generated from within the
brain itself, independent of (although affected by) sensory stimuli
Sleep and wake are not passive processes as once thought…
Why does RAS send so much output to:
Basal ganglia?
Thalamus?
Basal forebrain?
What NTs does RAS use?
RAS (in midbrain) & Pontomesencephalic system (pons & midbrain)
Receive sensory input from many ascending pathways
Send inputs to thalamus and basal forebrain
Releases ACh & Glutamate (Æ EPSEs) Æ increased arousal & W
e.g. nicotine (ACh agonist) Æ increased W and alertness
e.g. if basal forebrain damaged (e.g. Alzheimer’s Disease) Æ poor
attentional focus, impaired alertness, increased S (esp. SWS)
3. Turning Off Arousal and Turning On Sleep
How do we transition out of high arousal and into sleep?
Basal Forebrain Region & Anterior Hypothalamus
Both of these regions are together implicated in initiating sleep
Tumors/lesions in this area Æ difficulty initiating sleep, no more SWS
If stimulate BFR/AH Æ increased SWS
Neurons in this area are active only during sleep
Adenosine (a peptide NT) levels increase with prolonged W, and decrease
With S
Adenosine inhibits ACh neurons of the basal forebrain Æ less arousal
Adenosine may play a primary role in the onset/control of sleep
Neural Mechanisms of Sleep (p.3)
Turning Off Arousal & Turning on Sleep (cont.)
Why do we need to turn off wakefulness every so often?
Maybe cells need to replenish energy supplies…
Other neurotransmitters that may have something to do with going from W Æ S:
Histamine, GABA, and Orexin/Hypocretin
There are neurons that run from the hypothalamus to the basal forebrain
that use histamine as their NT
histamine Æ increased arousal
histamine antagonist drugs (“anti-histamines”) Æ less arousal, drowsiness
e.g. Benadryl (blocks H1 RS)
histaminergic neurons are very active during W, very inactive during S
(both during NREM and REM)
Cells in the basal forebrain and the hypothalamus also increase the release
of GABA Æ increased IPSPs (inhibition) in brain activity Æ decreased
Arousal Æ increased likelihood of S (esp. NREM and SWS)
GABA agonist drugs (e.g. sedative-hypnotics) (alcohol, barbiturates,
BZDs) Æ decreased arousal & increased likelihood of sleep
Role of orexin/hypocretin
Humans with a sleep disorder called narcolepsy have a great deal of
difficulty remaining awake & keep lapsing into sleep
At birth they have normal wake and sleep, but begin developing severe
EDS in adolescence typically
The onset of these symptoms coincide with the dying off of neurons
in their lateral hypothalamus that normally produce orexin (also
called hypocretin)
Is orexin/hypocretin a NT that promotes wakefulness?
Neural Mechanisms of Sleep (p.4)
4. Once Asleep, What Controls Sleep Stages? (“sleep architecture”)
Raphe Nuclei
Must be inactive for REM to occur
These are midline structures in the brainstem (near pontine/medullary RF)
Neurons are the major source of serotonin/5HT in the brain
These 5HT neurons are most active W, decrease their activity as become sleepy,
and then enter sleep
Almost no activity during REM except for the first seconds of REM sleep
when they are very active (even > than in W)
Give PCPA (parachlorophenylalanine) Æ totally blocks synthesis of 5HT
Æ decreased cortical arousal
Activity in Raphe neurons seems to inhibit REM
Nuclei in Pons/Medulla that Control REM Sleep
If transect brain anterior to pons Æ no REM
If transect brain posterior to pons Æ still see REM (alternating with SWS)
PGO spikes precede the onset of REM sleep (Pons, lateral Geniculate nucleus,
Occipital lobe)
At the start of REM, each PGO spike correlates with a single REM (rapid
eye movement)
Locus coeruleus (in dorsal pons region):
Like the Raphe nucleus, neurons in LC must be inactive for REM to occur
LC neurons most active in W, decrease their activity before SO, inactive in REM
Is the major source of nor-epinephrine NT
If stimulate just ventral to LC Æ abolishes REM sleep
If lesion LC Æ induces/prolongs REM sleep
Neurons in LC are inactive during REM sleep
NEURAL MECHANISMS OF SLEEP (cont., p.5)
Neurons that control REM use ACh (acetylcholine)
Cholinergic agonists Æ induces/prolong REM sleep (e.g. muscarine)
Cholinergic antagonists – reduce/block REM sleep (e.g. antidepressants)
Specialized nuclei in area of pons & medulla that control various aspects of
REM sleep:
To generate PGO spikes
To produce cortical EEG desynchronization (peribrachial area)
To generate hippocampal theta waves (5-8 Hz)
To produce muscle twitches in face, extremeties
To produce REMs
To produce skeletal muscle atonia (just ventral to LC)(subcoerulear nucleus)
To produce SNS arousal (cardiorespiratory irregularities)
If lesion subcoerulear nucleus Æ abolishes muscle atonia normally seen in REM
Jouvet’s cats got up and acted out their “dreams”(presumably)
If stimulate SN Æ profound atonia (descending axons in spinal cord terminate on
interneurons (Renshaw cells) that then inhibit alpha motor neurons Æ skeletal
muscle paralysis)
Note: this system uses nor-epinephrine as a NT
Peribrachial area sends axons to RF Æ which, in turn, sends axons to basal
forebrain (using ACh) Æ desynchronous beta EEG in cortex
PB area also Æ PGO spikes and REMs
PB area also Æ activates the SN Æ muscle atonia
Suprachiasmatic Nucleus of Hypothalamus
area in brain of circadian timing mechanism
nucleus contains neurons that exhibit circadian cycles of electrical activity,
metabolic activity, etc. (even when isolated from the rest of the brain)
neurons exhibit “endogenous” rhythm
Ss can be selectively bred to have shorter or longer rhythms
Transplant data
“light on” signals from SCN Æ pineal gland (suppresses melatonin production)
“light off” signals from SCN Æ pineal gland produces melatonin
Underlies the C-drive of sleep
Neural Mechanisms of Sleep (p.6)
SCN receives major inputs from retina (signaling L&D), major zeitgeber is light
Note: SCN is not the only brain area that can do this circadian timing, because
after lesioning the SCN Ss can still entrain to food or water availability
(although can no longer do so to L/D)
General Summary of some NTs:
In Wake – ACh, NE and 5HT are all in high amounts; glutamate & histamine high
Orexin/hypocretin high; adenosine accumulates
In NREM – ACh is low, and both NE and 5HT may be high; GABA high
In REM – ACh is high, and both NE and 5HT are low