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Comparative Physiology and Pharmacology of SleepSleep regulation (animals)

Reto HuberUniversity Children‘s Hospital

Bio 333: HS 2012; 29.10.2011

Learning objectives

At the end of the lecture you should be able to:

• Describe the homeostatic regulation of sleep in animals

• Understand mechanisms underlying sleep homeostasis

2

Sleep homeostasis

Achermann & Borbély 2003

Dose-dependent relationship

Sle

ep (m

inut

es)

Fruit fly

Duration of sleep deprivation

Huber et al., 2004

3

1 s1 mV

Franken et al., 1991

0 Hours 6 0 Hours 6

WNR

Slo

w-w

ave

activ

ity

Slow wave activity increase

Baseline Recovery after SD

Rat

After sleep deprivation

Hours of sleep deprivation

0 4 6100

110

120

130

140

%

BASELINE

C57BL/6J 129/OLA

After spontaneous waking

Duration of previous waking episode (min)

10-20 20-30 >30100

105

110

115

120% C57BL/6J 129/OLA

RECOVERY

Mouse

Dose-dependent relationship

Slo

w-w

ave

activ

ity

Huber et al., 2000

4

Independence from circadian effects

Tobler et al., 1983

After sleep deprivation

Suprachiasmaticnuclei

rest

-act

ivity

plo

t

increasing process: St+1=1-(1-St) * e -dt/Ti

decreasing process: St+1= St * e -dt/Td

WAKINGNREMSREMS

0250500750

100012501500

hours

0 12 24 36 48

NREMSWakingREMS

µV2

Simulation of process S

5

0.0

0.2

0.4

0.6

0.8

1.0

SIMULATIONDATA r=0.84

Huber et al., 2000

Slo

w w

ave

activ

ity

(tran

sfor

med

)

Hours0 6 12 18 24

Simulation of process S

The dynamics of sleep homeostasis can be quantified.

Sleep homeostasis in the animal kingdom

Tobler et al., 1983

Zebra fish

Zhdanova et al., 2006

Martinez et al., 2008

Cockroach

Pigeon

Sleep deprivation

BaselineSlo

w w

ave

activ

ity

(hours)

1 2 3 4 (¼ Night)

(hours) 1 2 3 4Loco

mot

ion

(Min

)/15

Min

6

Exceptions?

Gill et al., 2009

non-stop flight 8117–11 680 km

Lyamin et al., 2005

Killer wale Godwits (limosa) Mothers Calves

Per

cent

age

of n

ight

-tim

esp

ent r

estin

g

Sandpiper

Lesku et al., 2012

Sleep need is homeostatically regulated.

All investigated species show sleep homeostasis.

What is responsible for the increased sleep need?

7

Sleep deprivation may lead to death (?)

Rechtschaffen et al., 1993

„Sleep substance“

• Hypothesis: Hypnotoxin accumulates during waking and is metabolized during sleep (Piéron, 1913).

• Experiment: Injection of cerebrospinal fluid of sleep deprived sheep leads to increase of NREM sleep in rats (Pappenheimeret al., 1967).

• Factor S: Muramyldipeptide was identified from such cerebrospinal fluid (Pappenheimer et al., 1975; Krueger et al., 1982).

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Energy conservation

• Hypothesis: Replenishment of energy stores which were depleted during waking (Benington and Heller, 1995).

• It was postulated that Adenosine increases and Glycogen decreases during wakefulness.

• The increase of Adenosine leads to increased sleep need.

Long term potentiation(LTP)

Synaptic strength

Waking: Strengthening Sleep: Weakening

Synaptic scaling(downscaling)

Bliss & Lomo 1973 Turrigiano & Nelson 2004

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Synaptic Homeostasis

WakingNREMSREMS

Slo

pe (%

of m

ean)

Slo

pe (%

of m

ean)

Vyazovskiy et al., 2008

By Tononi and Cirelli, 2006

Rat

The synaptic homeostasis hypothesis unifies existing hypotheses about the function of sleep (sleep substance, energy).

The hypothesis provides direct explanation for the increase in slow wave activity.

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Synchronization of activity

t

Vyazovskiy et al., 2009

Early sleepLate sleep

Ratte: Multiunit Recording

Evidence for changes in excitability also exist for humans.

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Design

hd-EEG TMS NBS

TMS evoked potentials200 pulses

11 pm 8 am

Baseline

11 pm

Sleep deprivationTEP

Hd EEGSleep

All night

Recovery

8 am 8 am 11 pm

TEPTEP TEPTEPTEP TEP TEP

1 pm 1 pm

Study protocol

n=6

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Time course of cortical excitability