Sleep function and synaptic
homeostasis
Guilio Tononi, Chiara Cirelli
Seminar presentation
Kristjan-Julius Laak
March 2014
Today’s presentation
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The synaptic homeostasis hypothesis
The main claims in detail
Why does it matter?
Discussion about the hypothesis
The synaptic homeostasis hypothesis
Sleep is the price we pay for the placticity of our brain
nREM
{Slow wave} sleep plays {the main} role in the
regulation of synaptic weight in the brain.
The amount of influence the firing of one neuron has on another.
The hypothesis in brief
1. Wakefulness is associated with synaptic
potentiation enhancement in signal transmission between neurons
2. Synaptic potentiation is tied to the
homeostatic regulation of slow wave activity
(SWA)
3. Slow wave activity is associated with synaptic
downscaling
4. Downscaling is tied to the beneficial effects
of sleep on neural function and performance
Two-process model
Borbely & Achermann, 1999
Sleep is regulated by both the circadian component C (24h) and a homeostatic
process S
Homeostatic regulation
derived from
the SWA in
the EEG of
NREM sleep
total amount
of synaptic
weight in
cerebral
cortex
Schematic diagram of the synaptic
homeostasis
1. Synaptic potentiation
2. SWA
3. Downscaling
4. Benefits
The main claims in detail
1. Wakefulness is associated with synaptic
potentiation
2. Synaptic potentiation is tied slow wave
homeostasis
3. SWA is associated with synaptic downscaling
4. Downscaling is necessary for efficiency
1. Wakefulness is associated with
synaptic potentiation
• Plastic changes occur much of waking life
• The changes result more often in long-term
potentiation (LTP) than in long-term
depression
• Thus resulting in a net potentiation of synaptic
strength
Evidence
Animals in enriched environment ->
an increase in synaptic density ->
LTP-like molecular changes
Evidence
Local increases in synaptic density
Evidence
Induction of LTP genes during spontaneous
wakefulness VS. during sleep the genes are
almost abolished
Evidence
Human brain metabolism increases throughout
the wakefulness
Mechanisms
• Evolutionary: potentiation should happend
during wakefulness
• High-activity subset of neurons may give rise
to LTP-related gene expression and thus LTP
• Specific effect of noradrenaline, which is high
during waking period VS. absent during sleep
(important for LTP)
The main claims in detail
1. Wakefulness is associated with synaptic
potentiation
2. Synaptic potentiation is tied slow wave
homeostasis
3. SWA is associated with synaptic downscaling
4. Downscaling is necessary for efficiency
2. Synaptic potentiation is tied slow
wave homeostasis
• The higher the amount of synaptic
potentiation in cortical circuits during
wakefulness, the higher the increase in SWA
during subsequent sleep.
Or...
↑ Duration of wakefulness
↑ Expression of markers of synaptic
potentiation
↑ SWA
Evidence
For the same duration of wakefulness, more
exploring the environment- > SWA increased
Evidence
Lesioned noradrenergic system (less LTP)
-> less SWA
It is not wakefulness as such, but the induction of LTP-related
molecules normally associated with wakefulness, that is
responsible for driving the homeostatic increase in SWA
Evidence
Local effect of learning
-> increase in local SWA in that specific region
Evidence
Developmental studies:
SWA changes during the lifespan follows cortical
synaptic density (in adolescence)
Mechanisms
• Modeling studies show that stronger corticocortico connections result in stronger
activation of sodium dependent potassium
current, which leads to a longer down-phase
-> large amplitude.
The main claims in detail
1. Wakefulness is associated with synaptic
potentiation
2. Synaptic potentiation is tied slow wave
homeostasis
3. SWA is associated with synaptic downscaling
4. Downscaling is necessary for efficiency
3. SWA is associated with synaptic
downscaling
The slow waves promote generalized
depression/downscaling of synaptic strength
Evidence
The fact that EEG SWA decreased exponentially
during sleep is an evidence to synaptic
downscaling
Evidence
If SWA is suppressed in the first part of sleep, it
increases greatly in the second part
Evidence
Brain metabolism absolute levels decrease
during sleep
Evidence
Upregulation of molecules implicated in synaptic
depression
Sleep is not just unfavorable for synaptic potentiation, but
conductive to synaptic downscaling
Mechanisms
• Low frequency oscillations are ideally suited to
induce depotentiation i.e. depression in
stimulation paradigms
• Low frequency oscillations during sleep may
promote depression through changes in calcium
dynamics
• Temporal pairing of up-phase spiking and downphase may indicate to synapses that the input
was not effective in driving postsynaptic activity
• The process is self-limiting
The main claims in detail
1. Wakefulness is associated with synaptic
potentiation
2. Synaptic potentiation is tied slow wave
homeostasis
3. SWA is associated with synaptic downscaling
4. Downscaling is necessary for efficiency
The functional advantages of synaptic
downscaling during sleep
1. Energy savings
2. Space savings
3. Benefits for learning and memory
1. Energy savings
The higher the synaptic weight
-> the higher the energy budget
40% postsynaptic repolarization process
40% action potentials
2. Space savings
Synaptic strengthening is accompanied by
increased size of terminal parts,
and synapses may even grow in number.
3. Benefits for learning and memory
• Downscaling promotes synaptic competition.
E.g. development: stronger synapses survive.
• Signal-to-noise ratio grows when we sleep
(red synapses, 5 vs 150 etc)
3. Benefits for learning and memory
Acquiring new information is not possible if
there is no space.
Sleep would not only be the price we have to pay for plasticity
the previous day, but also an investment to allow the organism
learn afresh the next day.
Further questions need to be
addressed
• What are the complex relationships between the local
regulation of sleep as mediated by synaptic
homeostasis, and the global regulation of sleep as
mediated by hypothalamic and brainstem centers?
• How does the hypothesis apply to brain structures
other than the cerebral cortex, e.g. hippocampus?
Other species? (4h vs 20h)
• What is the role of REM sleep? (only part of the story)
• What is the role of sleep spindles?
• What happens if synaptic downscaling is incomplete?
Do other mechanisms intervene to reduce neuronal
excitability and thereby metabolic needs?