04.02 - Wake Genes that are Associated with Energy Metabolism

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来自 University of Michigan 的课程

Sleep: Neurobiology, Medicine, and Society

42 个评分

University of Michigan

Sleep: Neurobiology, Medicine, and Society

42 个评分

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.

从本节课中

Unit 04 - Neurobiology: Molecular Biology and Genetics of Sleep - (Honors Track)

Unit 4 closes out the Neurobiology section with a lecture from Chiara Cirelli, Ph.D. on Molecular Biology and the Genetics of Sleep. PLEASE NOTE: This content is only required for students who have chosen to pursue the Honors Track certification.

04.01 - Expression of mRNA Varies During Sleep and Wakefulness8:12

04.02 - Wake Genes that are Associated with Energy Metabolism 7:27

04.03 - Synaptic Plasticity is Genetically Modulated 7:55

与讲师见面

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

Let's focus now on the wake genes that involved in energy metabolism.

Early studies are using the RNA protection,

I say, in situ hybridization and differential display,

that already showed that indeed some mitochondria genes coded by

the mitochondrial genome are induced even just after three hours wake relative to sleep.

Here, you see, for instance,

the sub-unit 2 of NADH dehydrogenase and,

here, the sub-unit 1 of cytochrome c oxidase.

And the follow up studies show that it's not just that the amount of messenger RNA,

but even the activity,

the enzymatic activity of some of

these mitochondrial enzymes involved in the respiratory chain.

Here, you see cytochrome oxidase activity is increased

after a few hours of wake or sleep deprivation relative to sleep.

Of course, in one sense,

it's not surprising that there is upregulation of metabolic genes in

wake relative to sleep because we haven't known for

quite some time based on studies in primates,

as well as in humans,

studies using measuring glucose consumption,

as well as oxygen use, that, overall,

the energy needs of the brain are 20,

25 percent higher after wake than after non-rapid eye movement sleep or non-REM sleep,

which accounts for most 70 percent of all sleep.

And the reason why in wake,

there is increased energy demand is because an activity of

the excitatory glutamatergic cells in the brain is higher in wake than in sleep.

In the cerebral cortex, for instance,

up to 80 percent of neurons are glutamatergic excitatory neurons,

and up to 80 percent of all the oxidative metabolism of the brain

is used to meet the energy needs of those neurons.

The REMaining 10 to 20 percent are used for

glial activity and inhibitory GABAergic cells activity.

We also know that in resting conditions of quiet wake,

there is a very tight coupling between

glucose consumption in the brain and the glutamate to glutamine cycling,

which is a marker of glutamatergic activity.

And, here, you see an example of

how indeed excitatory activity in the cortex is higher during wake than during sleep.

You see here the scalp EEG,

the activated EEG during wake and these low waves of non-REM sleep.

Here, you see multi-unit activity spike activity from single neurons,

and it's obvious that these neurons are actively tonic and firing during wake,

as well as during REM sleep.

But during non-REM sleep,

they stop firing every half a second or

so during the periods of that so-called off periods.

And it is because of these periods of silence that, overall,

firing rates in the cortex are as shown here, 20,

25 percent or 30 percent lower in non-REM sleep relative to wake.

If we look at consistent with this finding,

the extracellular level of glutamate in the cortex,

and we measure how they change across the 24-hour sleep wake cycle using amperometry,

fixed potential amperometry, which is a technique with

very high temporal resolution of one second or so.

We can see that, overall,

glutamate levels are lower during the day

when the rat is mainly asleep and higher during the night.

And, also, that during each wake episode,

which is shown here in red,

glutamate levels that tend to increase and instead then they decrease

during the periods of non-REM sleep do increase again here and here,

for instance, during these green periods that correspond to the bouts of REM sleep.

By contrast, if we measured glucose levels in the extracellular space,

again, in the rat cortex,

they behave in the opposite way,

and so they tend to decline here during wake,

increase during non-REM sleep and decline again during REM sleep.

Let's now focus on the third category of genes,

which are those related to the cellular stress response.

Perhaps the most consistent finding across all species in all laboratories has been

the induction of this so-called stress response gene

BiP or HSPA 5 in wake relative to sleep.

BiP is part of the unfolded protein responses,

so it's induced in very known physiological situations, for instance,

in cases of significant calcium imbalance in the cell or glucose depletion,

and the induction of the UPR causes a slowing down of protein synthesis.

BiP is a chaperone in endoplasmic reticulum,

and the induction of these chaperone promotes in known physiological conditions,

the degradation of misfolded proteins.

However, BiP is also induced in very physiological conditions during which it

helps in the folding of newly normally synthesized proteins.

And there is evidence indeed, for instance,

in these very well characterized model of learning,

the long term and sensitization training Aplysia.

The BiP, as shown here,

is strongly induced after training in this model.

There is also recent evidence that BiP may be involved in the transfer

in the dendrite of the glutamatergic receptors that were mentioned before,

and that the entire induction of the UPR response is

helping and is promoting the surface expression of these receptors.

So, perhaps, it's not by chance that these genes are

all upregulated during waking because they might be strongly linked,

and they might all reflect a higher level

of activity and plasticity during wake relative to sleep.

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