Exam3Lec5SleepWakeCycles&CircadianRhythms Flashcards
True or false: Every organ and cell. has a circadian rhythm/clock
True
ex: hr drops when you sleep
What is the circadian clock ?
an internal (endogenous) biological time-keeping mechanism that coordinates numerous molecular, physiological, and biological processes with external time.
What are the 3 properties of circadian clocks?
- “Free-run” or persist in the absence of environmental cues (constant conditions) with a period of ~24 hours
- Temperature compensated
* Fluctuations in temperature DO NOT change the free-running (endogenous) period.
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.
Circadian Rhythm Parameters: What is ZT?
LD-entrained rhythm: System where natural time/oscillating environment (i.e. light/dark patterns throughout the day) are responsible for physiology.
Circadian Rhythm Parameters: What is CT?
Free-running rhythm: System where free running period/internal clock is responsible for physiology.
Definition of each:
1. Period
2. Free running period
3. Phase
4. Amplitude
- Period: The time it takes to complete a full cycle of a particular event.
- Free-running period (𝝉): The period at which a circadian rhythm runs absent entrainment cues.
- Phase: A specific time in a given cycle
- Amplitude: Strength of the rhythm from trough to peak
What structure is responsible for our internal clock (what is the central oscillator)?
the suprachiasmatic nucleus (SCN)
What is the fxn of the suprachiasmatic nucleus (SCN) and how is it entrained?
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 chias,
Surgical ablation of the SCN results in what?
loss of rhythmicity
What is there within every clock and what is its fxn?
The Core Mammalian Oscillator, is balances activating and inhibiting transcription factors (TF) and ultimately physiological factors.
What are the 2 arms of the Core Mammalian Oscillator?
Negative and Postive arm
What is the fxn of the negative arm of the The Core Mammalian Oscillator
Negative arm functions to give a 24-hour free running period.
* Core Activator: BMAL1/CLOCK
* Core Repressor: PER/CRY
What is the fxn of the positive arm of the Core Mammalian Oscillator?
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
Explain what is occuring in this image of the Core Mammalian Oscillator
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
What are Clocks Rhythm Sleep Disorders (CRSD) ?
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.
Comorbidity of CRSD
Associated long-term health problems, such as metabolic syndrome, diabetes, and Alzheimer’s
What are the 6 different types of CRSDs?
- Shift Work
- Jet Lag
- Delated Sleep Phase Syndrome (DSPS)
- Familial Advanced Sleep-Phase Syndrome (FASPS)
- Non-24-Hour Sleep-Wake Syndrome (N-24)
- Irregular Sleep-Wake Rhythm (ISWR)
Know ALL CRSDs in detail.
What is Jet lag and where does it stem from?
Disruption of the circadian rhythms due to crossing time zones.
Stems from a mismatch of the internal circadian clock and external time.
Traveling WEST requires what?
hy
“phase-delaying” our circadian rhythms – waking and going to bed LATER
hy
Easier to entrain.
Traveling EAST requires what?
hy
“phase-advancing” our circadian rhythms – waking and going to bed EARLIER.
hy
More difficult to entrain.
What is the rhytmicity shown in a wild type mouse during LD and DD?
LD: Normal
DD: Phase shift by 30 min (expected)
What is the rhytmicity shown in a mouse with a mutated Per2 (mPer2) –OR– Per1 (mPer1) during LD and DD?
LD: Normal
DD: Shortened free-running period and phase shift by about 2 hours.
What is the rhytmicity shown in a mouse with a mutated mPer1 AND mPer2) during LD and DD?
LD: Normal
DD: Completely arrhythmic
What happens to the rhytmicity with a BMAL1 knockout?
BMAL1 knock outs show similar results to that of mPer1 and mPer2 together.
LD: perfect rhythmicity thanks to light cues
DD: mice are completely arrhythmic
Explain the correlation between sleep/wake cycles and diurnal amyloid beta oscillations
A study measured mice at the beginning of onsset of AD and later onset of AD (9 months).
At the beginning, there were no Amyloid protein depositions, so they had a normal sleep wake pattern. Later around 9 months , mice have developed a severe case of AD with a significant incr in amyloid plaque deposits. It was shown that their circadian rhythm was completely messed up.
Results: Mice studies indicate how increased deposition of Aβ (as pathology progressed) lead to disruptions in the sleep/wake cycles.
Explain AD pts with sundowing and temperature rhythmicity
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.
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 other set of mice hat PS1mt with amyloid plaques.
Study:
* Normal: normal rhythmicity in CSF AB2. This is expected as PS1 is cleaving the protein and preventing buildup.
* PS1mt and removed amyloid plaques: rhythmicity remains relatively in-tact 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; its the amyloid plaques itself contributing, NOT mutation of PS1.
What were the results of the study using Tg4510 mice?
- Tg4510 mice saw significant changes in free running period and arrhythmicity during DD.
- Tg4510 also showed increased activity in the presence of light stimulus when compared to Ntg (normal) counterparts.
- TAU is also believed to impair Per’s ability to translocate into the nucleus and mediate appropriate circadian cycles.
- it impaired Pers ability to inhibit BMAL/CLOCK so BMAL keeps going so you see an incr in free running period and incr in arrythmic rhythm.
Explain how CK1 inhibitors impacted hippocampal fxn with the sponatenous alternation Y-maze experiment
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
