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
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
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)
Sleep to Wake What Causes the Switch? When?
(Saper et al.2011)
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? REM to NREM
(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
Sleep-to-Wake Transition
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)
The Goal: Integrated Model
Melatonin Interleukins
Ghrelin TNF∂ Leptin
Adosine Glucose/
BDNF Insulin
ACTH
DASN
DAVTA
NAcc
AChLDT
AChPPT
GABA2GABA2
Hist
Hcrt LCNPY
BF
Sleep-to-Wake Transition
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)
The Goal: Integrated Model
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