What is sleep for?Sleep and Neural Function

July 6th, 2007

An embarrassment of riches?

Immune Function

Muscle/organ Function

Toxin Removal

Energy Repletion

Somatic Regeneration

Neural RegenerationPredator Avoidance

Brain Cooling

Brain Development

Learning and Memory

Species Programming

Psychological Function

Ok, so maybe it does lots of things…who cares?

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Neuroscience and developmental biology are incomplete without an understanding of sleep function

Ethology is incomplete without an understanding of sleep function

Sleep medicine is incomplete without an understanding of sleep function

Sleep medicine matters

• 40 million Americans are chronically ill with various sleep disorders.

• Another 20-30 million American experience intermittent sleep-related problems.

• Estimated direct and indirect costs to society range from 15.9-100 billion dollars (1992).

From National Commission on Sleep Disorders Research (1992,1998)

Sleep is regulated and animals die in the absence of sleep

So why haven’t we figured it out?

Problem 1: Evolution and Adaptation

Is human sleep an accumulation of functions?

1O Function

2O Function

3O Function

4O Function

5O Function

6O Function

7O Function

9O Function

8O Functionnematodes

arthropods

chordates From Raizen, 2007

Problem 2: distinguishing function from interaction

Problem 3: disentangling sleep from the clock

Dijk and Schantz, 2005 ; Fuller et al., 2006; Zvonic, et al., 2007

First things first: we don’t sleep ‘cause there’s nothing else to do

Tackling the problem

• Clues from ontogeny

• Clues from the molecular biology

• Clues from phylogeny

REM

NREM

Clues from ontogeny: sleep is maximal when the brain is growing and

very plastic

Adapted from Roffwarg et al., 1966; Jouvet-Mounier, 1970

• membrane trafficking & maintenance

• cholesterol biosynthesis

• synaptic plasticity

Cirelli & Tononi, 2004

Clues from molecular biology – transcription

Clues from molecular biology – transcription

Guzman-Marin et al 1997

Nakanishi et al 1997

Clues from molecular biology – translation

Clues from phylogeny - In the beginning, there was sleep....?

• quiescencequiescence

• increased arousal increased arousal thresholds thresholds

• homeostatic homeostatic regulationregulation

A function that is simple and conserved?

Species Specific & Specialized Adaptations

Species Specific & Specialized Adaptations

Common Function ?

Do gifted and talented mollusks sleep to learn?

Brown et al., 2006

What about gifted and talented jellyfish?

Nerve ring

Nilsson et al., 2005

• unlike other cnidaria, box jellies have complex predatory behavior

• need for sleep-like state is seemingly dependent on hunting activity

So, do all species sleep to learn, or remember?

What people can tell us that other animals can’t...

Stickgold et al., 2000

What people can tell us that other animals can’t...

• "The night before Easter Sunday of that year I awoke, turned on the light, and jotted down a few notes on a tiny slip of paper. Then I fell asleep again. It occurred to me at 6 o'clock in the morning that during the night I had written down something most important, but I was unable to decipher the scrawl. The next night, at 3 o'clock, the idea returned. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission that I had uttered 17 years ago was correct. I got up immediately, went to the laboratory, and performed a single experiment on a frog's heart according to the nocturnal design."

- Otto Loewi

insights from big brains..

Huber et al., 2004

What (we think) we know

• Sleep is a brain phenomenon• Sleep contributes to adaptive changes in

the nervous system following experience• Sleep may be crucial during periods of

rapid brain growth and plasticity• Sleep may be a time when neurons are

rebuilt, remade, or tuned up• Sleep plays some role in learning and

memory

All of the big questions are unanswered

• Is sleep the same in all organisms? Is there any difference in function at the neuron level?

• Is sleep evolve once or many times?• Why can’t we do this stuff while were

awake?• Why REM and NREM sleep? Why do they

occur sequentially?• And what do REM and NREM do??

Its unclear where sleep contributes to learning and memory..

• Encoding• Storage

(consolidation, reconsolidation)

• Maintenance and stabilization

• Retrieval• Forgetting

• Declarative– episodic– semantic

• Non-Declarative– procedural/skill– conditioning

– priming– non-associative

What stages? What types?

What kind of activity is necessary? Chronic neuronal recording

Scalar measures and relation to sleep stage

Overview

• Developmental brain plasticity—what is it?• How we measure it.• What does sleep have to do with it (lots)?• How does this help us understand sleep

function?

Ocular dominance plasticity

• Occurs in the intact brain in vivo.• Produced by natural forms of inputs (changes in vision: not tetany in vitro).• Has adaptive signif icance to the animal (stereoscopic vision and acuity).• Can be tr iggered with a few hours of input (easy to design experiments).• Measured in standard ways in many labs.• Well described on a cellular level (NMDA receptors, kinases, etc.)• Has provided insights into brain plast icity across the l i fespan and in many

parts of the brain.

David Hubel Torsten N. Wiesel

Cortical plasticity triggered by MD: Optical maps

Non-deprived eye Deprived eye

Cortical plasticity triggered by MD: Unit physiology

0

50

100

1 2 3 4 5 6 7Ocular Dominance

Num

ber

of C

ells

0

50

100

MD

Normal: cortical neurons driven by both eyes

MD: most neurons driven by non-deprived eye

right eye left eyeBoth eyes

A simple experiment

• Experience (MD) only

• MD + ad lib sleep in dark

• MD + wake in dark

• 12 hours of MD

Sleep enhances loss of function in deprived eye pathways

Sleep-dependent plasticity requires cortical activity in sleep

Modified from Hata and Stryker 1994; Frank et al., 2006

What we know so far—and what we suspect.

Sleep Enhances ODP

Activity-dependent

CREBpathways?

NMDA, AMPAVGCCs,GABA?

PKA, cAMKII ERK

Calcineurin?

Genes up?

Genes down?

Protein synthesis?

ECM?

Changes in spines?

Activity changes

Thalamo-cort ical?

Intra-cortical?

Intrinsic or Network?

Excitatory/ inhibitory?

REM sleep? NREM sleep?

mgf@mail.med.upenn.edu

112 Johnson Pavilion Dept. of Neuroscience University

of Pennsylvania Philadelphia PA 19104

Dr.’s Naoum Issa and Michael Stryker

Dr. Sushil Jha: Reversible inactivation, chronic recording

Dr.‘s Sara Aton and Julie Seibt: NMDAR-protein synthesis

Past graduate students: Brian Jones, Laila Dadvand

Students: Nick Steinmetz

Lab technician: Tammi Coleman