neurobiology of sleep onset: the sleep-wake switch

How does sleep happen?Understanding “The Sleep Switch” Neurobiology

Awake Asleep

Waking Experience

Desynchronized, Aware

REM Sleep

Desynchronized, Unaware

NREM (Deep) Sleep

Synchronized, Unaware

What You Probably Know

Waking Experience

Desynchronized, Aware

REM Sleep

Desynchronized, Unaware

NREM (Deep) Sleep

Synchronized, Unaware

What You Probably Know

But what about the neurons that make these EEG patterns?

What Are You Talking About?● What is the “Sleep Switch”?

○ Does it exist?○ Neural populations involved?○ How does it work?

● Switching States: ○ Wake => Sleep○ REM => NREM

● Importance○ Disorders of “switching”

What is The “Sleep Switch”? ● Systems Theory:

○ Theoretical concept that sleep and wake are two, distinct mental states

○ feedback loop with circuits running in opposite

● The activity of each circuit inhibits activity from the other circuit in turn disinhibiting itself.

● Similar to a “flip-flow switches” in electronics

● Little to no transitional state: either on or off.

Good Theory, but so what?

(Rempe, Best, Terman, 2009)

Mathematical models replicate neuronal activity

Similar feedback loops in neural populations

Awake

REM

NREM

REM

Awake

Where do Switches Occur?Here Here Here Here

Awake

REM

NREM

REM

Awake

Where do Switches Occur?Here Here Here Here

HOWEVER: Most literature focuses only on this step.

Second, entering REM

The interrelationship of the two halves of the REM switch. The REM-off region is identified by the overlap of inputs from the orexin neurons and the eVLPO. These neurons in the vlPAG and LPT have a mutually inhibitory interaction with REM-on GABAergic neurons of the vSLD, but also inhibit REM generator circuitry in the remainder of the SLD and the PC. Note that cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT–LDT) are REM-on and may inhibit the LPT (as cholinergic agonists injected in this region cause REM states), but are not directly inhibited by it, and thus are not part of the mutually inhibitory flip–flop switch. Similarly, serotoninergic dorsal raphe and noradrenergic locus coeruleus (DRN–LC) neurons activate the REM-off circuitry, and thus monoamine re-uptake inhibitors, such as antidepressants, can dramatically suppress REM sleep. However, they also are not inhibited directly by the SLD, and hence are not part of the mutually inhibitory flip–flop switch

Remaining Literature Inconclusive

(Lu, et al. 2006)( de Lecea, Bourgin. 2006)

“A peptide-centric view of the reciprocal interaction model. The original reciprocal interaction model proposed that monoaminergic REM-off cells inhibit the activity of cholinergic REM-on neurons in the pontine reticular formation. Different revisions of the model have added GABAergic inhibition to these reciprocal interactions and modulation of the REM-off component by the extended VLPO. The discovery of the role of the hypocretins in narcolepsy and stability of wakefulness suggested that peptides could also play a relevant neuromodulatory role in this model. In this review we discuss the role of VIP, PACAP and Urotensin II as putative neuroregulatory elements of REM on neurons.

REM to NREM

The interrelationship of the two halves of the REM switch. The REM-off region is identified by the overlap of inputs from the orexin neurons and the eVLPO. These neurons in the vlPAG and LPT have a mutually inhibitory interaction with REM-on GABAergic neurons of the vSLD, but also inhibit REM generator circuitry in the remainder of the SLD and the PC. Note that cholinergic neurons in the pedunculopontine and laterodorsal tegmental nuclei (PPT–LDT) are REM-on and may inhibit the LPT (as cholinergic agonists injected in this region cause REM states), but are not directly inhibited by it, and thus are not part of the mutually inhibitory flip–flop switch. Similarly, serotoninergic dorsal raphe and noradrenergic locus coeruleus (DRN–LC) neurons activate the REM-off circuitry, and thus monoamine re-uptake inhibitors, such as antidepressants, can dramatically suppress REM sleep. However, they also are not inhibited directly by the SLD, and hence are not part of the mutually inhibitory flip–flop switch

(Lu, et al. 2006)( de Lecea, Bourgin. 2006)

“A peptide-centric view of the reciprocal interaction model. The original reciprocal interaction model proposed that monoaminergic REM-off cells inhibit the activity of cholinergic REM-on neurons in the pontine reticular formation. Different revisions of the model have added GABAergic inhibition to these reciprocal interactions and modulation of the REM-off component by the extended VLPO. The discovery of the role of the hypocretins in narcolepsy and stability of wakefulness suggested that peptides could also play a relevant neuromodulatory role in this model. In this review we discuss the role of VIP, PACAP and Urotensin II as putative neuroregulatory elements of REM on neurons.

REM to NREM

THIS? THIS??Remaining Literature Inconclusive

Sleep to Wake What Causes the Switch? When?

(Saper et al.2011)

What Causes the Switch? When? REM to NREM

(Saper et al.2011)

What Causes the Switch? When?

(Saper et al.2011)

The flip-flop switch:

Red = Inhibition

Green = Facilitation

Sleep-Wake States

“ sleep is an emergent property of populations of

local neural networks undergoing state

transitions”

Thus,

(Clinton et al. 2011)

So… Are We Done?Not even close!

Only SOME of the Key Brain AreasName AKA

Locus Cerlus LC

Turbomamalary N. TMN

Ventrolateral Preoptic Area VLPO

Basial Forbrain BF

Supraciasmatic N. SCN

Lateral Hypothalamic Area LHA

Perifornical area PeF

Name AKA

Periaqueductal gray PAG

Parabrachial nucleus PB

Medial Preoptic N. MnPO

Sublaterodorsal Tegmental N. SLD

Ventromedial hypothalamus VMH

Substantia Niagra SN

Ventral Tegmental Area VTA

DorsalMedial Hypothalmus DMH

Cerebral Cortex CC

Precoeruleus PC

Periventricular Hypothalmus? PVH

Dorsal Raphe N. DR

Lateral Dorsal Tegmentum LDT

pedunculopontine Tegmentum PPT

Name AKA

(De Lecue 2015)

What Different Systems Do

HcrtDA

Hist

Integrator A

Gatekeper(s) Pacemaker(s)

Effector(s)Facilitator(s) Theta

Facilitator(s) Gamma

Wake

Sleep

5HT

NE

Ach

ACTH

DASN

DAVTA

NAcc

AChLDT

AChPPT

GABA2GABA2

Hist

Hcrt LCNPY

BF

Sleep-to-Wake Transition

Ca1/3

POMC/CART

CRF

UtsnII

(De Lecue 2015)

The Goal: Integrated Model

ACTH

DASN

DAVTA

NAcc

AChLDT

AChPPT

GABA2GABA2

Hist

Hcrt LCNPY

BF


Ca1/3

POMC/CART

CRF

UtsnII

p .80

p .85

p .18

p .09

p .40

p .14p .39

p .05

p .44

p .68

p .22

p .41

p .73p .22 p .13

p .36

p .55

p .20

p .06

p .06

p .11

p .02

p .03

p .32

(De Lecue 2015)


Melatonin Interleukins

Ghrelin TNF∂ Leptin

Adosine Glucose/

BDNF Insulin

ACTH

DASN

DAVTA

NAcc

AChLDT

AChPPT

GABA2GABA2

Hist

Hcrt LCNPY

BF


Ca1/3

POMC/CART

CRF

UtsnII

p .80

p .85

p .18

p .09

p .40

p .14p .39

p .05

p .44

p .68

p .22

p .41

p .73p .22 p .13

p .36

p .55

p .20

p .06

p .06

p .11

p .02

p .03

p .32

(De Lecue 2015)


Impact

http://www.youtube.com/watch?v=-zVCYdrw-1o

Importance

Questions?

ReferencesLu J, Sherman D, Devor M, Saper CB (2006) A putative flip–flop switch for control of rem sleep.

Rempe, Best J, Terman D (2009) A mathematical model of the sleep/wake cycle.

Saper CB, Chou TC, Scammell TE (2001) The sleep switch: hypothalamic control of sleep and wakefulness.

Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms.

Phillips A, Robinson P (2008) Sleep deprivation in a quantitative physiologically based model of the ascending arousal system.

De Lecea. (2015) Presentation at The University Of Toronto, St George

Clinton, J., Davis, C., Zielinski, M., Jewett, K., & Krueger, J. (2011). Biochemical Regulation of Sleep and Sleep Biomarkers.

de Lecea L. (2012) Hypocretins and the neurobiology of sleep-wake mechanisms

neurobiology of sleep onset: the sleep-wake switch

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