Sleep function and synaptic homeostasis

Guilio Tononi, Chiara Cirelli

Seminar presentation

Kristjan-Julius LaakMarch 2014

Today’s presentation

• 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

{Slow wave} sleep plays {the main} role in the regulation of synaptic weight in the brain.

nREM

The amount of influence the firing of one neuron has on another.

The hypothesis in brief

1. Wakefulness is associated with synaptic potentiation

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

enhancement in signal transmission between neurons

Two-process modelSleep is regulated by both the circadian component C (24h) and a homeostatic

process S

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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 downscaling4. 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

EvidenceAnimals 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 downscaling4. 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 cortico-cortico 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 downscaling4. 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 down-phase 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 downscaling4. Downscaling is necessary for efficiency

The functional advantages of synaptic downscaling during sleep

1. Energy savings2. Space savings3. Benefits for learning and memory

1. Energy savings

The higher the synaptic weight -> the higher the energy budget

40% postsynaptic repolarization process40% 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?