Lecture 6 - Circadian Rhythms Flashcards

(75 cards)

1
Q

What is a sleep cycle?

A

24 hours with cues

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2
Q

What time period will a circadian rhythm be maintained in even in the absence of light and how was this discovered?

A

24 hr cycle; in a study in which they removed light cues they found that the sleep and wake period for humans was 25-26 hours and 23 hrs and they showed a shift in people would stay up later each day and wake up later; but when they reintroduced light cues there was entrainment

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3
Q

What to have in addition to our daily cycle of sleep and wake which is also controlled by our circadian rhythm?

A

melatonin levels
body temp
serum cortisol levels

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4
Q

Where is the central clock?

A

the SCN or suprachiasmatic nucleus (above the optic chiasm)

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5
Q

What three pieces of evidence proved that the SCN is the master clock?

A
  1. neurons in the SCN fire APs in a 24 hour rhythm and isolated SCN neurons continue to keep this rhythm (meaning this occurs intrinsically)
  2. ablation of the SCN disrupts wake/sleep cycle in mice
  3. transplanted SCN confers time keeping of host to recipient (if you transplant the SCN of a mouse on a different time cycle to another cycle you can change the rhythm of the mice)
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6
Q

How was it proven that isolated SCN neurons maintain 24hr circadian rhythm?

A

-used calcium indicator like Fura2
-put a calcium indicator into the cell and could measure the calcium firing throughout the day and they found that the calcium firing would go up and down depending on the time of day in a circadian rhythm

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7
Q

What did the APs show from the isolated SCN neurons?

A

that they would fire in a circadian rhythm in a 24 hr rhythm and if you put TTX it would stop, but then wash it away it would restore

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8
Q

Why are hamsters good to study for circadian rhythms?

A

they are nocturnal and they run at night

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9
Q

In mutant flies that had a disrupted circadian rhythm what was the mutant gene found and what did they show?

A

the per gene was mutant (for period) and they showed no rhythm in darkness

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10
Q

Mutations in the per gene in rodents also found what to be disrupted?

A

the circadian rhythm; there is another gene as well which is called Clock - need to note that the WT have a rhythm which is less than 24 hours in constant darkness and the mutant has a cycle of 24 hrs mutation in clock animals still maintained circadian rhythm

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11
Q

What does the per gene a part of?

A

the clock in the SCN

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12
Q

What does the per gene encode?

A

a transcription factor

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13
Q

What is a transcription factor?

A

a protein that can turn on genes and causes them to be transcribed to RNA

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14
Q

How many distinct per genes are in some species that have similar functions?

A

2-3 distinct per genes

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15
Q

What length of a cycle does the per protein and per mRNA have?

A

a 24 hr cycle

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16
Q

The level of the per mRNA and per protein are found to vary at different times throughout the day?

A

the per mRNA is highest in the day and the proteins levels are delayed by 6 hours so they peak at dusk

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17
Q

When a per promoter was driving the fluorescent gene Luc bioluminescence what was observed?

A

-that it gets brighter and dimmer throughout the day in the same circadian rhythm over seven days

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18
Q

What does the promoter upstream of the genes do?

A

binds a transcription factor Eric h then turns on a gene by promoting its transcription from DNA to mRNA

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19
Q

How many different gene can a transcription factor affect?

A

the expression of many genes and can bind to many genes

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20
Q

What are transcription factors where are they made and how do they get to the nucleus?

A

small proteins which are made in the cytoplasm and translocated to the nucleus

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21
Q

What is the molecular clock or transcriptional network made of?

A

4 transcription factors that act as dimers in two transcriptional networks to generate a 24 hour cycle of transcription

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22
Q

How do per (+cry) turn off?

A

they turn themselves off which takes some time since the mRNA need to make protein which needs to enter the nucleus and takes 6 to 12 hours
-they inhibit their transcription by taking off clock and bmal

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23
Q

What turns the per gene back on?

A

clock +cycle (bmal)

note that cycle is the fly version of bmal

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24
Q

What is a quick summary of the molecular clock or transcriptional network?

A

-DNA when transcribed is going to get mRNA and make the per protein’ there is another similar gene called cry which also gets transcribed and is made in the cytoplasm and they both gets translocated into the nucleus; various ways that you can make a clock and how you can make it out of genes and DNA and cells and there is a negative feedback that is critical to the clock so that the per protein once it makes it into the nucleus turns off its transcription so you Strat having less per and then something else then turns back on the per which is the clock and cycle which are transcription factors which bind to the per gene and turn per back on (ignore Tau in the diagram)

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25
What is the circadian rhythm in per mRNA and protein levels?
per mRNA levels grow during the day and the protein levels peak at night which means that when per enters the nucleus it blocks its own expression and these changes happens in both diurnal and nocturnal animals
26
How do we do from oscillations in level of per to daily oscillations in electrical activity? What are four proposed mechanisms?
ion channel expression distribution or functional properties must change 1. synthesis and degradation of ion channels 2. trafficking 3. distribution clustering or decluttering of ion channels 4. phosphorylation to activate the ion channels
27
How is the clock entrained?
light will come in through the eye through non image forming retinal ganglion cells or ipRGCs and this will change the activity of the SCN which will then input to our internal organs
28
Can the clock be reset instantaneously?
the clock cannot be reset instantaneously and it can only be tweaked one hour or so every day
29
What does light entrainment observed in the absence of rods and cones indicate?
that there is a third class of photoreceptor in the eye in addition to rods and cones and that is melanopsin and it is a light sensitive receptor
30
Where was melanopsin first found and also later found?
first found in frog skin and it is found in the mammalian retina in RGCs
31
How were melanopsin expressing cells identified?
LacZ reporter which is blue which was expressed under the melanopsin promoter and found melanopsin expressing RGC
32
Where do melanopsin cells project through and terminate?
-they project through the optic chiasm and terminate in the SCN
33
What type of cells are essential for circadian entrainment?
melanopsin retinal ganglion cells
34
What toxin receptor was expressed under melanopsin promotor to prove melanopsin loss leads to loss of light entrainment?
the diphtheria toxin and the diphtheria toxin receptor
35
What did the KO of melanopsin prove in regards to light entrainment and why?
KO of melanopsin does not impair light entrainment; rods and cones provide input to ipRGCs and this explains why the melanopsin KO has no effect on entrainment
36
Where do ipRGCs synapse and what do they cause?
-synapse in the SCN and they cause a change in intracellular signaling in SCN neurons that affects elements of the clock to speed or slow it down
37
What is familiar advanced sleep phase disorder?
-a genetic disorder of the circadian rhythm in which parents go to sleep at 6PM and they awake at 4AM -associated with the subtle mutations in the per gene that cause it to accumulate more quickly which shorten the clock
38
What is another genetic disorder of circadian rhythms or "clock mutations" in which the per gene does not accumulate as quickly which lengthen the clock?
delayed sleep phase syndrome
39
What is sleep?
naturally occurring state characterized by reduced or absent consciousness, have relatively suspended sensory activity, and inactivity of nearly all voluntary muscles
40
How many stages of sleep are there and how were they discovered?
5 stages of sleep and they were described in 1937 by Alfred Lee Loomis and his coworkers which performed EEG on subjects at night
41
What is REM sleep?
rapid eye movement sleep in which they are sharp spikes of activity
42
What is the relationship between REM sleep and dreaming?
by waking subjects during REM and non-REM sleep researchers were able to determine that dreams were accompanied by REM activity; dreaming more likely during REM sleep than non-REM sleep
43
What does each sleep stage have and provide and example of this in the awake state versus stage IV?
each stage has a specific wave form the awake state is less synchronized activity while stage IV is due to synchronized activity due to all cells firing at the same tome
44
How long is one sleep cycle and what does each successive cycle experience?
90mins; each successive cycle experiences longer REM stages
45
What three things occur during REM sleep?
rapid eye movements dreaming muscle paralysis
46
What occurs during Stage 4 of sleep?
largest slow oscillations in the EEG with 2 bouts per night and is considered the most restorative
47
What is REM sleep in regards to the brain and body versus nonREM?
REM - active brain in inactive body Non-REM - inactive brain in active body
48
During REM sleep how is motor activity inhibited?
descending pathways synapse onto and inhibit motor neurons in the spinal cord
49
What does sleep help us do?
consolidate memories
50
In the finger tapping task in which subjects type a simple numeric sequence on a computer as quickly and accurately as possible or have to touch their fingers in a particular order proved what in regards to sleep and the consolidation of learning?
that a good night's sleep provided improvement in the task by 20%
51
What study proved that sleep was essential?
In a study in which a rat can sleep and another one cannot because every time the rat tries to sleep a platform rotates; the rat died and they even lost weight even though they were eating more. Summary rats forced to stay awake lose weight and die in 3-4 feels
52
What is the longest time a human has voluntarily stayed awake?
19 days
53
What was found encephalitis did to patients in regards to sleep?
it attacked regions of the brain that regulate sleep and wakefulness which lead to the coining of sleeping sickness -caused a lesion in the ascending system in the brainstem-reticular activating system
54
If you stimulate the ascending brainstem-reticular activating system what happens?
the animal is awake
55
If you stimulate the thalamus what happens?
the animal is asleep
56
What is the relationship between the ascending brainstem-reticular activating system and the thalamus and sleep?
the ascending brainstem reticular activating system inhibits the thalamus which causes or induces sleep
57
What do antihistamines do and what do histamines do?
antihistamines cause sleepiness histamine is used as a neurotransmitter by the brain area which promotes arousal
58
What is histamine made by?
the TMN or tuberomamillary nucleus
59
Where do wakefulness centers send their projections through?
the cortex
60
What is narcolepsy?
recurring short episodes of sleep that are accompanied by cataplexy which is an abrupt loss of muscle tone in response to strong emotion
61
What is sleep apnea and how is it treated?
obstruction of upper airways due to loss of muscle tones and leads to frequent awakening and also snoring -treated with a mask to deliver positive air pressure
62
What is insomnia?
an inability to sleep caused by many factors
63
What is delayed sleep phase syndrome and advanced sleep syndrome?
alterations in the circadian rhythm due to mutations in the per gene or other components of the clock
64
What are the symptoms of narcolepsy?
excessive daytime sleepiness, sudden loss of muscle tone (cataplexy); sleep paralysis and hallucinations (when falling asleep or waking up)
65
A mutation in what receptor is associated with causing narcolepsy and what is the role of this receptor?
mutation in the orexin receptor gene leads to narcolepsy in dogs and mice -orexin plays a role in increased food intake and increases wakefulness
66
What is orexin and what is it produced by?
peptide neurotransmitter and produced by cells in the hypothalamus
67
What is another term for orexin?
hypocretin
68
Where do the cells in the hypothalamus that produce orexin send their projections to?
many brain centers which control the activity of the brain
69
How many orexin receptor types are found throughout the brain and what type of receptors are they and what type of activity do they lead to?
two orexin receptors GPCRs excitatory activity
70
What is expressed under the hypocretin promoter Hcrt which is another name for orexin?
channel rhodopsin
71
What does light do in cells that normally express orexin?
light opens a channel in these cells and it produces depolarization and the firing of APs
72
What does direct activation of orexin cells with light produce and was this found?
wakefulness; found that with direct selective optogentic photo stimulation of orexin neurons using fiber optics increased the probability of the transition to wakefulness from either slow wave sleep or rapid eye movement sleep
73
What causes narcolepsy in mice and dogs and how can they be treated?
mutation in the orexin receptor or loss of the orexin peptide; can provide the peptide to cure it or mutate the receptor
74
What causes narcolepsy in humans?
loss of orexin neurons cannot provide orexin peptide as therapeutic relief in this case
75