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Neurobiology of Sleep

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Ashley Shemery

on 26 April 2015

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Transcript of Neurobiology of Sleep

The Waking Brain
The Sleeping Brain
The Sleep Homeostat
Circadian Regulation
Extra Info & Summary
Neurobiology of Sleep
von Economo & Encephalitis Lethargica
More common outcome
Patients slept 20+ hours
Less common
Patients slept just a few hours a day
How did the same disease cause opposite problems?
Affected different parts of the brain!
Lesions of the midbrain & posterior hypothalamus
Lesions of the basal forebrain & anterior hypothalamus
There seem to be two separate systems at work!
1) Brain circuitry controlling wakefulness
2) Brain circuitry controlling sleep
The Waking & Sleeping Brain
Ascending Arousal System
VLPO projections to the Ascending Arousal System
How do we know our waking mechanisms are ascending?
Ascending Reticular Activating System (ARAS)
Roles of the First Branch (shorter path)
1) Clears pathway for thalamic sensory transmission
Role of the Second Branch (longer path)
1) Removing a the part of the brainstem at the pontomesencephalic results in a coma
2) Stimulating the rostral pontine reticular formation produces the type of EEG you see when someone is awake or in REM sleep
Fiber system ascends from rostral & dorsal pons to the midbrain, then splits into 2 branches

Consists mainly of cholingeric neurons (ACh). Stems from the pedunculopontine & laterodorsal tegmental area into the thalamus
2) Consists mainly of monoaminergic neurons. Stems from the upper brain stem & caudal hypothalamus and projects into the lateral hypothalamic area, basal forebrain & cerebral cortex --- Skips the thalamus!
Necessary for consciousness, alertness & sleep
2) Because of rapid neural firing during wake & REM some believe this system is the origin of cortical EEG
However, most believe the ARAS doesn't actually regulate the activity in this thalamic area. Instead it gates sensory input based on sleep, wake or REM
Ventrolateral medulla
Locus coeruleus (LC)
Ventral periaqueductal gray matter (vPAG)
Dorsal & median raphe nuclei (DRN & MnRN)
Tuberomammillary nucleus (TMN)
Lateral Hypothalamic Area (LHA)
Has a pretty complex communication network
Very important in arousal system! Lesions to this area cause profound sleepiness & even coma
LHA neurons have 2 major neuropeptide systems:
Melanin-concentrating hormone (MCH)
Basal Forebrain (BF)
Melanin-concentrating horomone (MCH)
Active during wakefulness
Lack of orexin causes narcoleptic-type behavior -- but still allows normal amounts of sleep & wake
Active mostly during REM sleep
Inhibit the monoaminergic systems (which we know are crucial for remaining awake)
But even without MCH we still have normal amounts of sleep & wake
Given that neither orexin nor MCH seem to affect amounts of sleep or wake there must be some other group of neurons maintaining wake in the LHA
Orexin Control
REM Sleep Circuitry
As von Economo predicted...
There are separate wake & sleep systems!
Ablations or lesions of the preoptic area of the brain caused profound insomnia
Specifically the vetolateral preoptic nucleus (VLPO)
Contains inhibitory neurons: GABA & galanin
Communicates w/ major monoamingeric systems
REM Sleep
NREM Sleep
Projects to pontine tegmentum
Projects to monoaminergic systems & LHA neurons
The Flip-flop Switch
One more thing ---> Median Preoptic Nucleus (MnPO)
Contains GABAnergic, glutaminergic, & nitric oxide neurons
Fire during REM & NREM --- Quiet during wake
The GABAnergic project to same ascending arousal system as the VLPO
A mix of cholinergic & non-cholinergic (mostly GABA-nergic) neurons
Project mostly to the hippocampus & little bit to the thalamus
Inhibition of the area
Stimulation of the area
Slows down EEG
Activates EEG
Orexin plays a big role in the wake cycle
Without it, people experience very fragmented & sudden bouts of sleep
But orexin neuron don't project into the VLPO
LHA orexin is external to the flip-flop... instead it seems to just help
the switch
REM / Paradoxical sleep / Active sleep
Reciprocal interaction model (Cholinergic-monoamingergic model)
Didn't hold up -- may be involved but aren't sufficient or necessary
Non-monoaminergic systems involved in maintaining wakefullness
Summary of the Waking Brain
We know it's an ascending mechanism b/c destroying low/pontine level structures results in coma or excessive sleepiness
This ascending mechanism (ARAS) consists of 2 major branches:

The first branch
acts as a gate for sensory input to the thalamus... allows inputs to cross depending on wake, REM, or sleep
The second branch
consists of a huge monoamine system, sending excitatory neurons all the way up to the cortex
Additionally, the second branch consists of orexinergic neurons that are important for stabilizing wakefulness.
The basal forebrain seems to have a role in regulating EEG
REM Flip-Flop!!
Basal Forebrain

Spinal Ventral Horn
The REM Switch in Words
The vlPAG & the LPT make up the REM-OFF area of the brain. When awake or not in REM, this area actively sends GABAergic neurons to the REM-ON area
The PC & PB along with the SLD make up the REM-ON area of the brain.
There is an area called the eVLPO which houses some REM-ON neurons
To initiate REM sleep, this area sends inhibitory neurotransmitters to the REM-OFF area, this then causes the "switch"
Now, the REM-ON area sends its GABAergic neurons to the REM-OFF area, helping to inhibit it's activity
Additionally, the REM-ON area sends it glutaminergic neurons to the Spinal Ventral Horn
The Spinal Ventral Horn contain relay neurons which are almost always inhibitory
Thus glutaminergic neurons activate these inhibitory relay neurons causing total muscle atonia
Also, the REM-ON area sends glutaminergic neurons to the basal forebrain... the function of this is not well known
Historical Theories
"The ability or tendency of an organism or cell to maintain internal equilibrium by adjusting its physiological processes"
Injecting spinal fluid of sleep deprived dogs into rested dogs caused the rested dogs to fall into deep sleep
Discovered two sleep promoting properties within spinal fluid:
1) Cytokine interleukin-1 (IL-1)
2) Tumor necrosis factor alpha (TNF)
Problem? Conflicting evidence for whether or not these substances build up during wakefulness & breakdown during sleep
What's the evidence?
Accumulates in brain tissue after ATP metabolism

Increased levels in cerebral cortex & basal forebrain during prolonged wakefulness
Acts on A1 receptors which are inhibitory
Acts on A2a receptors which activates sleep promoting neurons in the VLPO
When Adensoine A1 or A2a receptors are knocked out, the sleep drive is unaffected
The circadian drive as a drive toward wakefulness
Homeostatic Drive
Circadian Drive
Two-Process Model
Process C
Process S
In normal conditions, these two drives are aligned with one another
However, time travel, all-nighters, etc. cause them to become unaligned
So the question becomes which process exhibits the drive for wake and which exhibits the drive for sleep?
Initial "Evidence"
Forced desynchrony
Biological rhythms started free-running
Found that they got sleepy at the usual time and awake at the usual time
Ambiguous Evidence... This shows that the circadian drive could be a drive toward wakefulness or towards sleep
Suprachiasmatic Nucleus (SCN)
Our biological clock located in the hypothalamus
Contains over 20,000 neurons that fire in a 24 hour cycle
Manages the rhythms of several biological & physiological processes
Corticosterone levels
Melatonin levels
Meal times
Locomotor activity
Neural circuitry of the SNC provides slightly more convincing evidence
Neural Circuitry
subparaventricular zone (SPZ)
The circadian drive is a distinct process from the homeostatic drive
Unlike the homeostatic drive, it is thought to be a drive toward wakefulness
It is regulated by the SCN which does not directly link to any sleep or wake promoting areas
It has a complex connection to the DMH which then directly projects inhibitory neuroms to the VLPO & excitatory neurons to the LHA
Summary of Sleep & Wake Drives
Homeostatic drive is assumed but yet to be demonstrated without flaws
The most convincing contributor to this drive is adenosine b/c it accumulates across the day & binds to recptors located in seep promoting areas
The circadian drive is thought to be a drive towards wakefulness
It is not directly tied to wakefulness, but instead has a complex circuitry that eventually projects to wake promoting areas
This may be a middle ground for maintaining diurnal & nocturnal circadian rhythms
Summary of Sleep & Wake
GABA agonists
Bind to receptors in the VLPO but not the major arousal systems & show slow EEG
NMDA Antagonists
Bind to receptors in the wake areas of the brain & show wake EEG
High doses = sedation. VLPO contains kappa & mu receptors (wake & sleep)
The brain consists of an ascending arousal system which promotes wakefulness
It also consists of a sleep system which inhibits the arousal system
Our sleep & wake systems function like a switch, firmly shifting from one to the other w/o much transition
The smoothness of this switch is regulated by orexin
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