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Neuroscience: Exam 3 > Lecture 5: Sleep Wake Cycles & Circadian Rhythms > Flashcards

Lecture 5: Sleep Wake Cycles & Circadian Rhythms Flashcards

1
Q

True or false: Every organ and cell has a circadian rhythm/clock

A

True

ex: hr drops when you sleep

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2
Q

What is the circadian clock ?

A

an internal (endogenous) biological time-keeping mechanism that coordinates numerous molecular, physiological, and biological processes with external time.

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3
Q

Why is the Circadian Clock important?

A

Perturbations in normal circadian clock function are associated with many diseases and disorders

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4
Q

What are the 3 properties of circadian clocks?

A
  1. “Free-run” or persist in the absence of environmental cues (constant conditions) with a period of ~24 hours
  2. Temperature compensated
  • Fluctuations in temperature DO NOT change the free-running (endogenous) period.
  1. Entrained or reset by various environmental or external stimuli.
  • Light, temperature, and feeding

Temperature does not affect the period but it can affect the phase.

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5
Q

Circadian Rhythm Parameters: What is ZT?

A

LD-entrained rhythm: System where natural time/oscillating environment (i.e. light/dark patterns throughout the day) are responsible for physiology.

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6
Q

Circadian Rhythm Parameters: What is CT?

A

Free-running rhythm: System where free running period/internal clock is responsible for physiology.

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7
Q

Definition of each:
1. Period
2. Free running period
3. Phase
4. Amplitude

Circadian Rhythm Parameters

A
  1. Period: The time it takes to complete a full cycle of a particular event.
  2. Free-running period (𝝉): The period at which a circadian rhythm runs absent entrainment cues.
  3. Phase: A specific time in a given cycle
  4. Amplitude: Strength of the rhythm from trough to peak
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8
Q

Define Free-Running Period

A

The persistence of biological rhythms in the absence of an environmental cue (aka “free-running” rhythm)

Human Free-Running Period: Normally longer than 24 hr, changes as we age

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9
Q

What structure is responsible for our internal clock (what is the central oscillator)?

A

the suprachiasmatic nucleus (SCN)

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10
Q

What is the function of the suprachiasmatic nucleus (SCN) and how is it entrained?

A
  • Coordinates the timing of all other physiological clocks.
  • Given its proximity to the optic chiasm, the central oscillatory is entrained primarily by light

mediates every organ and cells clock in our body
located behind the optic chiasm,

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11
Q

Surgical ablation of the SCN results in what?

A

loss of rhythmicity

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12
Q

What is present within every mammalian clock and what is its function?

A
  • The Core Mammalian Oscillator
  • Function: Balances the activating and inhibiting transcription factors (TF) and ultimately physiological factors.
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13
Q

What are the 2 arms of the Core Mammalian Oscillator?

A

Negative and Postive Arm

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14
Q

What is the function of the negative arm of the Core Mammalian Oscillator? And list the core activator and core repressor.

A

Negative arm functions to give a 24-hour free-running period.

  • Core Activator: BMAL1/CLOCK
  • Core Repressor: PER/CRY
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15
Q

What is the function of the positive arm of the Core Mammalian Oscillator? And list the core activator and core repressor.

A

Positive arm functions to stabilize the negative arm in terms of oscillation strength and amplitude.

  • REV-ERBs (Repressors)
  • RORs (Activators)

mediating fxn; can strengthen or inhibit

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16
Q

Explain what is occuring in this image of the Core Mammalian Oscillator

BMAL/CLOCK: Green/Blue RORs: Purple PER: Yellow REV-ERBs: Red CRY: Orange
A

During the day: BMA1L/CLOCK (core activators) TF bind to BOX elements which triggers the transcription and translation of PERs and CRY (core repressors). At this time, however, CK1 is at high levels which ultimately leads to phosphorylation and degradation of the core repressors. In the absence of PER/CRY, BMAL1/CLOCK can activate cell specific physiological function (Primary Output) (ex: uch as those that decr HR)

At night: CK1 levels are relatively low which decr phosphorylation/degradation of PERs and CRY (core repressors). This allows PER and CRY to dimerize. They are then translocated to the nucleus where they can repress the binding of BMAL/CLOCK onto box elements.

REV-ERBS and RORs play more of a “maintenance” role where they can activate/repress the negative arm as needed in order to alter oscillation strength and amplitude. (Secondary Output)

basically:
day-CK1 lvls high, phosphorylates core repressions, BMAL1/CLOCK can continue transcription
night : CK1 lvls low phosphorylation of core repressiors dont occur, core reprosses dimerizes and translocated to nucleus , BMAL1/CLOCK cannot continue transcription

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17
Q

What is Chrontype?

A
  • Describes the timing of an individual sleep/wake pattern (Early bird vs. Night owl)
  • Changes as we age
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18
Q

What are Clocks Rhythm Sleep Disorders (CRSD)?

A

A class of sleep disorders characterized by a defect in sleep timing as defined by the Diagnostic and Statistical Manual (DSM-5) of mental health Disorders and in the International Classification of Sleep Disorders.

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19
Q

Comorbidity of CRSD

A

Associated long-term health problems, such as metabolic syndrome, diabetes, and Alzheimer’s

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20
Q

What are the 6 different types of CRSDs?

A
  1. Shift Work
  2. Jet Lag
  3. Delayed Sleep Phase Syndrome (DSPS)
  4. Familial Advanced Sleep-Phase Syndrome (FASPS)
  5. Non-24-Hour Sleep-Wake Syndrome (N-24)
  6. Irregular Sleep-Wake Rhythm (ISWR)

Know ALL CRSDs in detail.

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21
Q

What is Shift Work/Forced Circadian Desynchrony?

CRSD

A
  • Occurs when the circaidian clock is out of sync with external time d/t keeping a schedule that is misaligned with individual’s circadian rhythm (e.g. night shift, adolescence)
  • Linked to numerous diseases and disorders
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22
Q

What is Jet lag and where does it stem from?

A

Disruption of the circadian rhythms due to crossing time zones.
Stems from a mismatch of the internal circadian clock and external time.

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23
Q

Traveling WEST requires what?

HIGH yield

A

“phase-delaying” our circadian rhythms – waking and going to bed LATER (Ex. From Florida to California)

Easier to entrain.

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24
Q

Traveling EAST requires what?

HIGH yield

A

“phase-advancing” our circadian rhythms – waking and going to bed EARLIER. (Ex. Florida to France)

More difficult to entrain.

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25
Q

What is DSPS?

A

Delayed Sleep Phase Syndrome: Extreme “night owls” w/ sleep onset consistently between 2 and 6AM.

  • Mutations on Per3 and Clock have been implicated
26
Q

What is FASPS?

A

Familial Advanced Sleep-Phase Syndrome: Extreme “morning person” w/ sleep onset between 7 and 9PM and awakening prior to 5AM.

  • More common in elderly
  • Mutations in Per2 have been associated with FASPS
27
Q

What is N-24?

A

**Non-24-Hour Sleep-Wake Syndrome (Free-Running Disorder):
* Chronic pattern of daily delays in sleep onset and waking times.
* Primarily occurs in individuals who lack photic entrainment (blind).

28
Q

What is ISWR?

A

Irregular Sleep/Wake Rhythm: Lack of observable sleep/wake pattern (arrhythmic) w/ normal total sleep time.

29
Q

Diseases and Disorders Impacted by Circadian Function

Shiftwork has been classified as causing what type of disease?

A

cancer
Shiftwork has been classified as a probable carcinogen by the International Agency for Research on Cancer (IARC)

30
Q

List the possible CRSD Treatments (4)

LOW yield

A

Chrono-therapy- Progressive advancement or delay of sleep until an ideal schedule is reached

  • Behavioral Modifications
  • Bright Light Therapy
  • Pharmacological Interventions

Review Slide 37

31
Q

What are 3 metabolic disorders that can occur when circadian function is disrupted?

A
  1. Individuals exposed to a 28-hour LD schedule, which simulates jet lag and shift work, show impaired glucose tolerance and hyperleptinemia.
  2. Sleep disruption by waking subjects up in the middle of various sleep phases has been shown to impair glucose tolerance.
  3. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinemia and diabetes.
32
Q

How does time of day impact immune response and vaccines?

A

Time of day can be important for strength of an immune response.
Studies show that receiving a vaccine later in the day can lead to a stronger immune response.

33
Q

What is the general method of measuring activity of mice?

A
  1. Mice are placed in an incubator (light-tight enclosure) and you measaure the activity onf mice based on diff light exposures
  2. First one is LD: this is a normal 12 hours light/dark cycle so it mimics a normal day
  3. Second light exposure is DD: this is light off competely.
34
Q

At baseline, what is the free-running period of a mouse?

A

23.5 hours

35
Q

What was the activity of the mice during LD and DD?

A

LD: the mice normaly had more activity during the night and no activity during the day
DD: the mice relied solely on internal clock as opposed to entrained light cues. So the phase shifed by about 30-minutes every day.

36
Q

What is the rhytmicity shown in a wild type mouse during LD and DD?

A

LD: Normal
DD: Phase shift by 30 min (expected)

37
Q

What is the rhytmicity shown in a mouse with a mutated Per2 (mPer2) –OR– Per1 (mPer1) during LD and DD?

A

LD: Normal
DD: Shortened free-running period and phase shift by about 2 hours.

38
Q

What is the rhytmicity shown in a mouse with a mutated mPer1 AND mPer2) during LD and DD?

A

LD: Normal
DD: Completely arrhythmic

39
Q

What occurs when you remove Per from the internal clock?

A

When you remove Per you remove the “brake” which keeps the internal clock balanced. So things go completely crazy hence the arrhythmias.

We have our internal clock that can function on its own and we have an internal clock that takes external cues. We get rid of those external cues (DD) and if there are issues w/ factors of the internal clock (mPer1/2)= arrhythmia

40
Q

What happens to the rhytmicity with a BMAL1 knockout?

A

BMAL1 knock outs show similar results to that of mPer1/mPer2.
LD: perfect rhythmicity thanks to light cues
DD: mice are completely arrhythmic

41
Q

Explain real-time luminescence in cells

A

We can isolate an individual cell (ex. heart cell) and transduce luminescence protein into the cell. Protein will emit light during activity and not emit light w/ no activity

42
Q

Explain real-time luminescence in various tissues

A
  • Real-time luminescence can be done at the macro level where we transduce luminescence gene/protein into PER gene in the mouse
  • Any cell that carries the PER gene in the mouse will light up during activity. Research demonstrated activity in various tissues that had the PER gene such as SCH, kidney, cornea, liver, lung, and pituitary.
43
Q

Which Circadian Rhythm Sleep Disorders (CRSD) is associated with AD?

A

Generally, Delayed Sleep Phase Syndrome (DSPS)

Phase delay of sleep and core body temperature.

44
Q

What is sundowning?

A

AD pts experience time dependent increase in confusion, restlessness and delirium.

45
Q

How are melatonin levels affected in AD pts?

A

Melatonin levels are lower and rhythmicity of melatonin expression from the pineal gland is lost, even though the pineal glad isn’t effected by AD.

46
Q

Explain SCN pathology in AD pts

A

SCN pathology can be severe with significant deterioration evident in late stages.

47
Q

Explain the correlation between sleep/wake cycles and diurnal amyloid beta oscillations

A
  • A study measured mice at the beginning of the onset of AD and later onset of AD (9 months).
  • In the beginning, there were no Amyloid protein depositions, so they had a normal sleep-wake pattern.
  • Later around 9 months, mice developed a severe case of AD with a significant increase in amyloid plaque deposits. It was shown that their circadian rhythm was completely messed up.

Results: Mice studies indicate how the increased deposition of Aβ (as pathology progressed) leads to disruptions in the sleep/wake cycles.

48
Q

Explain AD pts witn sundowing and temperature rhytmicity

A

Patients experiencing sundowning (a symptom of AD) showed impaired rhythmicity of body temperature when compared to patients who have never experienced sundowning.

temp fluctuations messed up for AD with sundowning

AD pts with no sundowning showed normal temp rise during day and temp fall at night.

49
Q

What is the role of PS1 in regards to amyloid plaques? What occues if PS1 is mutated?

A
  • PS1 is an enzyme responsible for cleaving of Alpha-synuclein 42 and prevents it from forming amyloid plaques.
  • Any mutation to this enzyme leads to accumulation of amyloid plaques and is thus associated with AD pathology.
50
Q

Explain the results of the study where one set of mice with a normal functional PS1, another set of mice that has PS1mt and removed amyloid plaques, and another set of mice hat PS1mt with amyloid plaques.

A

Study:

  • Normal: normal rhythmicity in CSF AB2. This is expected as PS1 is cleaving the protein and prevents buildup.
  • PS1mt and removed amyloid plaques: rhythmicity remains relatively intact in the absence of amyloid plaques.
  • PS1mt with amyloid plaques: lost all rhythmicity,
    Results: There is a connection between AD pathology and changes in sleep/wake cycles; it’s the amyloid plaques itself contributing, NOT mutation of PS1.
51
Q

what tau gene was inserted into mice to show correlation b/w tau protein and circadian rhythm?

A

Used transgenic Tg4510 mice (Tau model) which carry mutant alleles that lead to expression of Tau at levels 16x normal, so mice developed AD.

52
Q

What were the results of the study using Tg4510 mice?

A
  1. Tg4510 mice saw significant changes in free running period and arrhythmicity during DD.
  2. Tg4510 also showed increased activity in the presence of light stimulus when compared to Ntg (normal) counterparts.
  3. TAU is also believed to impair Per’s ability to translocate into the nucleus and mediate appropriate circadian cycles.

  1. it impaired Per’Aability to inhbibt BMAL/CLOCK so BMAL keeps going so you see an incr in free running period and incr in arrythmic rhythm.
53
Q

How does CK1 contribute to AD pathology? How does it present?

A

CK1 also contributes to the formation of AB plaques and Tau (neurofibrillary) tangles.

  • In AB pathology this presents as shortened period length.

Remember: CK1 is important for phosphorylating and degrading PER (core repressor), specifically during the day.

54
Q

What are 3 fxns of CK1 Inhibitors (PF-670462)?

A
  1. Stabilizes PER levels
  2. Restore (increase) period length
  3. Decrease AB protein deposition in the hippocampus
55
Q

Explain how CK1 inhibitors impacted hippocampal fxn with the spontaneous alternation Y-maze experiment

A
  • Mice with amyloid plaques showed poor performance during spontaneous alternation Y-maze.
  • AB plaques in the hippocampus are associated with decreased cognitive function.
  • Mice with injected CK1inhibitors CK1i led to decreased AB deposition in the hippocampus.
  • They showed improved performance in the spontaneous alternation Y-maze
56
Q

Explain how CK1 inhibitors impacted hippocampal fxn with the contextual learning experiment

A
  • The hippocampus plays a role in contextual learning. In AD pathology, AB plaques in the hippocampus can inhibit ability to learn context cues during fear conditioning.
  • Administering CK1i led to decreased AB deposition in the hippocampus and ultimately, improved ability to learn context during fear conditioning.

contex learning is restores w/ CK1 inhib and removes amy plaques

mice with amy plaqes couldnt learn and did not associate purple box with pain. Gave the mice CK1 inhib and learning was restores.

57
Q
  1. The circadian clock, an internal biological time keeping mechanism, can be entrained or reset by various environmental or external stimuli. Which of the following external stimuli has the greatest effect on our circadian clock?
    A. Light
    B. Temperature
    C. Feeding
    D. Sound
A

A. Light

58
Q
  1. Sleep scientists at the Morsani College of Medicine are studying the effects of specific transcription factors within the core mammalian oscillator. If they were interested in silencing the “core repressors” of this system, which of the following transcription factors should they target?
    A. BMAL1/CLOCK
    B. REV-ERBs
    C. PER/CRY
    D. RORs
A

C. PER/CRY

59
Q
  1. Which of the following best describes the effect of a BMAL1 knockout on circadian rhythmicity within mice?
    A. Normal rhythmicity during DD
    B. 30-minute phase shift during LD
    C. Arrhythmicity during DD
    D. Shorted free-running period during LD
A

C. Arrhythmicity during DD

60
Q
  1. An MSP3 student is traveling west to California following finals. Naturally, the change in time zone leads to a mismatch between her internal clock and the external time. Which of the following describes the best way to adjust to this change?
    A. Phase-advancing; Waking and going to bed earlier
    B. Phase-delaying; Waking and going to bed later
    C. Phase-advancing; Waking and going to bed later
    D. Phase-delaying; Waking and going to bed earlier
A

B. Phase-delaying; Waking and going to bed later

61
Q
  1. All of the following are true regarding the use of CK1 inhibitors for the treatment of Alzheimer’s disease EXCEPT:
    A. Decrease period length to stabilize rhythmicity
    B. Stabilize PER levels within the mammalian oscillator
    C. Decrease AB protein deposition in the hippocampus
    D. Improve contextual learning and cognitive function
A

A. Decrease period length to stabilize rhythmicity

62
Q

Define Free-Running Period

A

The persistence of biological rhythms in the absence of an environmental cue (aka “free-running” rhythm)

Human Free-Running Period: Normally longer than 24 hr, changes as we age

Neuroscience: Exam 3 (9 decks)

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