The objective of this course is to give students the most up-to-date information on the biological, personal, and societal relevance of sleep. Personal relevance is emphasized by the fact that the single best predictor of daytime performance is the quality of the previous night's sleep. The brain actively generates sleep, and the first section of the course is an overview of the neurobiological basis of sleep control. The course provides cellular-level understanding of how sleep deprivation, jet lag, and substances such as alcohol, ,caffeine, and nicotine alter sleep and wakefulness. The second section of the course covers sleep-dependent changes in physiology and sleep disorders medicine. Particular emphasis will be placed on disorders of excessive sleepiness, insomnia, and sleep-dependent changes in autonomic control. Chronic sleep deprivation impairs immune function and may promote obesity. Deaths due to all causes are most frequent between 4:00 and 6:00 a.m., and this second section of the class highlights the relevance of sleep for preventive medicine. The societal relevance of sleep will be considered in the final section of the class. In an increasingly complex and technologically oriented society, operator-error by one individual can have a disastrous negative impact on public health and safety. Fatigue-related performance decrements are known to have contributed as causal factors to nuclear power plant failures, transportation disasters, and medical errors.
02:10: Summary
Loading...
來自 University of Michigan 的課程
Sleep: Neurobiology, Medicine, and Society
37 個評分
從本節課中
Unit 02 - Neurobiology Section: Neurobiology of Sleep and Wakefulness (Part Two) - (Honors Track)
Unit 2 continues the lecture from Helen Baghdoyan, Ph.D. on the Neurobiology of Sleep and Wakefulness. PLEASE NOTE: This content is only required for students who have chosen to pursue the Honors Track certification.
與講師見面
Ralph Lydic, Ph.D.Professor Emeritus, Molecular and Integrative Physiology, Professor Emeritus, Anesthesiology
University of Michigan Medical School
Helen Baghdoyan, Ph.D.Professor Emeritus, Anesthesiology, Professor Emeritus, Pharmacology, Professor of Psychiatry
University of Michigan Medical School
Hello. We finally arrived at the summary.
What I'm going to do now is put
together in an overview in a few slides what we've learned.
This table summarizes the state dependent neuronal discharge patterns
that we've talked about.
You see in the left column the discharge types that we've talked about,
the cell locations where the cell bodies for
those kinds of discharge patterns are located in the middle column,
and on the right, the transmitters that are
released by cells with those discharge patterns.
Now, if you look in the bottom row,
the only transmitter we haven't talked about on this list is dopamine.
Dopamine cell bodies located in the ventral tegmental area and the substantia nigra.
Dopaminergic neurons in these two-brain nuclei
have a state independent discharge pattern.
In other words, they don't change the firing rates across the sleep wake cycle.
And yet we know from pharmacological studies that
dopamine is a wakefulness-promoting transmitter.
So, there's more work to do to understand the role of dopamine in sleep cycle control.
I've included it on this table,
even though we didn't talk about it,
just so I could mention the fact that dopamine is clearly wakefulness promoting.
It's an area for future studies.
To wrap this up,
people are creating models.
People are now looking at how do we get our hands around,
how all these transmitters interact,
how do we describe and quantify the interactions of
these transmitters that generate states of sleep and wakefulness.
And there are mathematical models that are developed.
Dr. Booth reviews those models in her lecture.
I'm going to talk about the first brainstem model,
the first one that was based on cellular data and a mathematical model.
I'm not going to review the math.
I'm going to leave that for Dr. Booth.
I'm going to talk about just in a descriptive level,
and I'm going to review the forebrain system interactions that we talked about,
and I'm finally going to conclude by putting
the forebrain and brain stem circuits together all in
the non-quantitative way as a way of
summing up and pointing out where we need to go in the future.
So this scheme entices the reciprocal interaction model,
which was put forth by Hobson and McCarley,
and has been updated since its original publication in 1975.
And this is a model for the brainstem control of REM sleep.
What I'm going to do is, again,
go through this as a story model almost,
not as a mathematical model.
Dr. Booth will review the math with you.
So this model explains how REM sleep is generated based
on the activity of these neurons in the locus coeruleus and the dorsal raphe,
the wake on neurons,
the cholinergic neurons in the LDT PPT,
the REM-on population, the pontine reticular formation,
effector neurons, which are glutamatergic,
and the role of GABA within the pontine reticular formation in regulating sleep.
So since this is a cycle, it's non-REM-REM cycle.
We could start anywhere.
I'm going to start here with the wake on neurons.
One other element that in order for you to understand this
is again that these pathways are indicated by solid lines.
If there is a line at the end,
it means the signal is inhibitory and if there is an arrow at the end,
it means the signal is excitatory.
So when these monoaminergic wake on neurons fire,
they have recurrent collaterals,
so they are self inhibitory.
During waking,
these monoaminergic populations in the serotonergic and neurotenergic neurons fire,
then they also diminish their own activity via these recurrent collateral.
So they start to turn themselves off.
When the monoaminergic neurons turn off,
that causes a disinhibition of the cholinergic REM-on neurons.
So this normal inhibitory signal is with
withdrawn disinhibiting these cholinergic neurons and letting a fire.
Once the cholinergic neurons are disinhibited,
they have projections that are excitatory,
they release acetylcholine and excite pontine reticular formation neurons,
which are glutamatergic and these are the REM effector neurons.
Those effector neurons that are activated now to turn on RAM,
send projections back to the LDT and PPT and those projections are excitatory.
So we have a loop here,
sort of a feed forward loop,
for continuing to generate REM sleep.
Another thing that happens when
these pontine reticular formation effector neurons
begin to fire as a result of cholinergic stimulation,
these are glutamatergic projections that activate
GABAergic neurons, REM-on GABAergic neurons.
These are neurons in the dorsal raphe and locus coeruleus
that act to inhibit the wake on neurons.
So we're having yet another force to drive REM sleep generation.
As the cholinergic LDT PPT neurons continue
to fire and they're driven to fire to drive REM sleep,
they send projections to the pontine reticular formation
that activate M2 subtypes of muscarinic receptors.
These receptors are inhibitory and these M2 receptors are known to be localized
to GABAergic neurons within
the pontine reticular formation that are the REM-inhibitory GABAergic nuerons.
So by activating an inhibitory receptor,
one inhibits the REM-inhibitory neurons.
By inhibiting the REM-inhibitory neurons,
one then disinhibits further the pontine reticular formation REM effector neurons.
So this is a circuit for how REM is turned on and generated and maintained.
How we turn the circuit off?
Well, one way is that when
these cholinergic neurons fire to drive REM sleep, they also excite.
They send excitatory projections to the wake on neurons,
and this really is the reciprocal interaction portion of
the model that the cholinergic neurons then turned
back on the wake on neurons that were inhibiting REM and
those wake on neurons and start to fire and they turn off the cholinergic neurons.
So that's a summary of the reciprocal interaction model based on cell
firing data and based on pharmacology and chemistry experiments.
That circuit is redrawn here because now,
what I'm going to do is put it together with the forebrain circuit.
So here's the circuit we just reviewed.
I've redrawn it so that I can put it together with what's happening in the forebrain.
So, now I'm adding in
the forebrain systems that we reviewed and we'll go through those briefly.
Here are the GABAergic neurons in
the optic area and to your hypothalamus basal forebrain.
These are the ventrolateral preoptic area and then
median preoptic nucleus neurons that we talked about that are not REM-on.
Those neurons send inhibitory projections to
the hyper-cholinergic neurons in
the lateral hypothalamic area inhibiting these wake on neurons.
The other thing these GABAergic neurons do is send
inhibitory projections to the wake on
histaminergic monoamine neurons in oppose to your hypothalamus.
Likewise, the histamine neurons send inhibitory projections to the sleep on neurons,
so there's a mutual inhibition between the wake on
neurons and the non-REM-on neurons in the forebrain.
In addition, these non-REM-on neurons inhibit
the wakefulness promoting neurons of
the lateral hypothalamic area that contain hypocretin.
The lateral hypothalamic area neurons are shown of course sending
excitatory projections to the wakefulness-promoting histaminergic neurons.
And there's also an interaction between
the basal forebrain cholinergic neurons and
the lateral hypothalamic neurons that's mutually excitatory,
and the TMN histamine cells also excite the basal forebrain cholinergic neurons.
When we put the forebrain and the brainstem together as we are now being able to do,
this is what we begin to see.
The inhibitory GABAergic neurons in that drive non-REM sleep
send projections to the cholinergic neurons
and inhibit those cholinergic neurons in the brain stem.
These GABAergic sleep on neurons also send
projections to the way promoting dorsal raphe and locus coeruleus.
So that's one mechanism by which GABA from the forebrain turns off
the wakefulness-promoting system in addition to inhibiting the lateral hypothalamus.
We also know that the lateral hypothalamus activates the wake-promoting systems within
the pontine reticular formation within
the dorsal raphe and locus coeruleus and within the LDT PPT,
and we know interestingly that there are
inhibitory projections from the dorsal raphe
and locus coeruleus to the lateral hypothalamus.
So Dr. Booth is going to review for you some of the models that begin to
explain how these connections interact to drive states of sleep and wakefulness.
And I'm going to end now by saying that it's very exciting.
We've learned a lot and it's very exciting
for future research to continue to map the connections,
the cell discharge patterns,
the transmitters, and begin to come up with a way
that we can quantify the interactions between
transmitters in different brain regions to further elucidate
the neurochemical and neurobiological basis of sleep cycle control.
I want to thank you very much for your attention.
