child & youth Mental Health Series - CHEO ED Outreach · Synaptic Homeostasis – Long-term...

Today’s topic: Functions of Sleep in Humans and the Animal Kingdom

Speaker: Dr. Addo Boafo

child & youth

Mental Health Series

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Declaration of conflict

Speaker has nothing to disclose with regard to commercial support.

Speaker does not plan to discuss unlabeled/ investigational uses of commercial product.

Acknowledgments

Chloe Stevens, Bachelor of Health Science at Carleton

University, CHEO volunteer

Objectives

1) To learn about how to define and measure sleep

2) To learn about the Neuronal Group Theory of Sleep

3) To learn about six of the presumed functions of sleep

Defining and Measuring Sleep Across the

Animal Kingdom

Behavioural

Electrophysiological

Molecular

Metabolic

Neurotransmitter

Six Criteria of Sleep (Flanigan, 1973)

1. Preferred posture

2. Behavioural quiescence

3. Rapid state reversibility

4. Decreased responsiveness to surroundings (elevated

arousal threshold)

5. Homeostatic regulation (Campbell & Tobler, 1984):

rebound with increased sleep intensity or duration after

sleep loss

6. Electrical changes in brain’s activity in sleep

Behavioural and

Electrophysiological

Findings

Mammals

a) Electrophysiology

b) Neurotransmitters

c) Hormones

(Rasch & Born, 2013)

Molecular Manifestations of Sleep

The following are gene expressions increased during

wakefulness (Collingridge, Issac, & YWang, 2004, in Hinard

et al., 2012):

a) Immediate Early Genes (IEG) such as Homer (an expression gene),

Arc, Dbp and others, as well as genes expressing glucose

metabolism, lipid metabolism, cell cycle inhibitors (for example

apoptosis)

b) Plasticity-related gene expressions (and increased trafficking and

phosphorylation of postsynaptic glutamatergic AMPA receptors

containing GluRI subunit)

Metabolic Manifestations of Sleep

The following are increased during wakefulness (Hinard et

al., 2012):

a) Oxygen consumption

b) Glucose consumption

c) Metabolites (by-products) such as Alanine and Lactate (by-

product of glycolysis); Lysolipids (reflect membrane breakdown)

Neurotransmitter/Hormonal Manifestations

of Sleep

(Joiner, 2016)

Where Does Sleep Begin?

Central Nervous System

Individual Neuron

Group/Network of Neurons

Whole Brain

Half Brain

Local areas of Central Nervous System

Findings Supporting the Neuronal Group

Theory of Sleep

a) Whales, dolphins, migrating birds

b) Human traumatic brain injuries, strokes, etc.

c) Local sleep in awake rats (Vladyslav, 2011)

d) C. elegans (a worm, 1 mm long)

e) Neurons grown in the lab

C. elegans

1 mm in length

302 neurons

No complex structures such

as brain

Anatomy of a Neuron

Nucleus

Axon

Dendrites

Synapses

Synaptic cleft

Myelin sheath

Two Neuron Network

Glial cells outnumber

neurons 3:1

Glial cells start out as

precursor cells

Example of Neurons Grown in a Lab

(Hinard et al., 2012)

Functions of Sleep

There are several questions, for example:

a) Why do we need to sleep?

b) Why do some animals sleep at night and others during the day?

c) Why the “zoning out”/ relatively unconscious state?

d) Why does the armadillo sleep 20 hour and the wild African

elephant matriarch only 2 hours?

e) Does sleep exist to serve single neurons, a network/group of

neurons, the whole brain, whole body – do other organs or

structures such as the liver and kidney sleep?

Functions of Sleep

“Press reset button”

“Boost memory consolidation”

“Boost memory of immune system”

“Energy conservation”

“Sweep and Clean up the garbage”

“Service and Repair wear and tear”

Synaptic Homeostasis

(Wolf et al., 2016)

Activity at Synaptic Cleft

(Electrical/Chemical)

(Kruger et al., 2016)

Synaptic Homeostasis – Long-term

Potentiation

Persistent increase in synaptic strength following high

frequency stimulation of chemical synapse – product of:

1. Increase in number of release sites (increases synaptic strength)

2. Presynaptic release probability (increases synaptic strength)

3. Bigger (stronger) postsynaptic electrical response to release

transmitters (increases synaptic strength)

Sleep Boosts Memory Consolidation

Driven by Slow Wave Activity (less than 4 Hz)

Likely occurs early in sleep

Certain skills have the biggest boost – puzzle, piano/guitar

(Rasch & Born, 2013)

(Rasch & Born, 2013)

Sleep Improves Memory Forming Immune

Response

Boost likely if slow wave sleep is within 36 hours of

inoculation

Confirmed for Influenza and Hepatitis A and B inoculation

Adaptive Immunity

(Lange et al., 2011)

The Concept

Encoding: uptake of the antigen by APCs

Consolidation: two cell combo between APC and T helper

cell (immunological synapse); redistribution into long-

term storage

Recall: two cell types formed; B cells (produce antibodies)

and cytotoxic T cells work together to facilitate an

immune response upon reencounter of antigen

Hepatitis A and B virus, as well as influenza virus

(Lange et al., 2011)

Sleep Function - Energy Conservation

During sleep:

a) Reduction in energy expenditure of 7-69% among different

mammals (Toutain, Toutain, Webster, & McDonald, 1977)

b) Energy expenditure up by 7% in first 24 hours of sleep deprivation

c) Energy expenditure down by 5% during 8 hour recovery sleep

d) Energy expenditure up by 32% during sleep deprivation (Jung et

al., 2011)

Action Potentials

Human brain – 20-25% total body

energy expenditure

80% of brain energy used for

action potentials

Action potentials: electrical

currents generated by neurons

Human brain – 2% of total body

weight

Energy Conservation

Passive/Inactive Process (Berger & Phillips, 1995):

respiration rate, heart rate, gut motility, muscle activity

It is an active process (Schmidt, 2014) – Energy allocation

hypothesis

Energy Conservation - HydroOttawa

Model

Sleep Functions as Waste Management

System

Discovered in 2012 by Nedergaard

et al.

Components: as in image on right

Space between neurons increase

during sleep, allowing the brain

to flush out toxins that build up

during waking hours

Glia shrink during sleep

Sleep Functions as Waste Management

and Plumbing System

Increased circulation in mice CSF during sleep

60% increase in interstitial space

95% decrease in tracer activity during waking hours

2015, in mice posture lateral more than supine

(Xie, 2013)

Sleep Functions – Maintenance and

Repairs

Repair of neurons (Bellesi et al., 2013)

Repair of DNA (Bellesi et al., 2016)

Gene (DNA) Damage

Summary of the Functions of Sleep

“Press reset button”

“Boost memory consolidation”

“Boost memory of immune system”

“Energy conservation”

“Sweep and Clean up the garbage”

“Service and Repair wear and tear”

Practical Applications and Comments

Inoculations (flu)

Exams: piano or guitar

Alzheimer factor (amyloid-beta)

On-call physicians and local sleep phenomenon

Sleep deprivation relieves depression (temporarily)

Citations

1. Bellesi, M., Bushey, D., Chini, M., Tononi, G., & Cirelli, C. (2016). Contribution of sleep to the repair of neuronal DNA double-strand breaks: evidence from flies and mice. Scientific Reports, Rep 6: 36804, 1-13.

2. Bellesi, M., Pfister-Genskow, M., Maret, S., Keles, S., Tononi, G., & Cirelli, C. (2013). Effects of sleep and wake on Oligodendrocytes and their precursors. The Journal of Neuroscience, 33(36), 14288-14300.

3. Berger, R. J., & Phillips, N. H. (1995). Energy conservation and sleep. Behavioural Brain Research, 69, 65-73.

4. Campbell, S. S., & Tobler, I. (1984). Animal sleep: a review of sleep duration of across phylogeny. Neurosci. Biobehav. Rev, 8, 269-300.

5. Collingridge, G. I., Isaac, J. T.,YWang, Y. T. (2004). Receptor trafficking and synaptic plasticity. Nat Rev Neuroscience, 5, 952-962.

Citations

6. Flanigan Jr. W. G. (1973). Sleep and wakefulness in iguanid lizards. Ctenosaura pectinata and Iguana iguana. Brain, Behaviour and Evolution, 8, 401-436.

7. Hinard, V., Mikhail, C., Pradervand, S, Curie, T., Houtkooper, R. H., Auwerx, J. et al. (2012). Key Electrophysiological, Molecular, and Metabolic Signatures of Sleep and Wakefulness Revealed in Primary Cortical Cultures. The Journal of Neuroscience, 32(36), 12506-12517.

8. Joiner, W. J. (2016). Unraveling the Evolutionary Determinants of Sleep. Current Biology, 26(Oct. 24), R1073-R1087.

9. Kruger, J. M., Frank, M, G., Wisor, J. P., & Roy, S. (2016). Sleep function: Toward elucidating an enigma. Sleep Medicine Reviews, 28, 46-54.

10. Lange, T., Dimitrov, S., Bollinger, T., Diekelmann, S., & Born, J. (2011). Sleep after vaccination boosts immunological memory. Journal of Immunology, 187, 283-290.

11. Nedergaard, M. (2013). Garbage truck of the brain. Science. 340, 1529-1530.

Citations

12. Rasch, B., & Born, J. (2013). About sleep's role in memory. Physiological Review., 93, 682. 27

13. Schmidt, M. H. (2014). The energy allocation function of sleep: a unifying theory of sleep, torpor, and continuous wakefulness. Neuroscience and Biobehavioural Review, 47, 122-153.

14. Toutain, P. L., Toutain, C., Webster, A. J., & McDonald, J. D. (1977). Sleep and activity, age and fatness, and the energy expenditure of continued sleep. British Journal of Nutrition, 38, 445-454.

15. Vyazovskiy, V. V., Olcese, U., Hanlon, E. C., Nir, Y. Cirelli, C., & Tononi, G. (2011). Local sleep in awake rats. Nature, 472, 443-447.

16. Wolf, E., Kuhn, M., Normann, C., Mainberger, F., Maier, J. G., Maywald, S., et al. (2016). Synaptic plasticity model of therapeutic sleep deprivation in major depression. Sleep Medicine Reviews, 30, 53-62.

17. Xie, L., Kang, H., Xu, Q., Chen, M., Liao, Y., Thiyagarajan, M. et al. (2013). Sleep drives metabolite clearance from the adult brain. Science, 18(342), 1-11.