Circadian Rhythm Flashcards
what are actograms?
graphical representations used in circadian rhythm research to visualize activity patterns over time
what do actograms typically show?
- x-axis: time (hrs or days)
- y-axis: activity level (quantified and plotted as counts per time)
- data points: represents the activity level at the specific time (i.e., wheel rotations)
what are entrainments?
show how an organism’s activity rhythm synchronizes with external cues such as light-dark cycles, feeding times, or temperature changes.
When an organism’s activity rhythm is synchronized with an external cue, it demonstrates a stable and predictable pattern over time.
how could an actogram provide evidence for a self-sustaining endogenous circadian pacemaker?
- Free-Running Rhythm: In the absence of external time cues (such as light-dark cycles), the organism should continue to exhibit a rhythmic pattern of activity that persists close to, but not exactly, a 24-hour cycle (consistent peaks at the same times each day -> shows that its internally regulated)
- Period Length: The period length of the free-running rhythm should remain relatively constant across multiple cycles.
- Phase Shifts: When exposed to external time cues, such as changes in light-dark cycles, the organism’s activity rhythm should be capable of adjusting or “entraining” to these cues by shifting its phase.
Persistence in Constant Conditions: Even when placed in constant environmental conditions (e.g., constant darkness), the organism should maintain its rhythmic activity pattern, demonstrating that its circadian rhythm is not simply a response to external stimuli but is generated internally.
what does left bending in an actogram mean?
occurs when the activity onset or offset times of an organism’s circadian rhythm occur earlier each day compared to the previous day.
This can indicate a circadian rhythm with a period length slightly shorter than 24 hours, often referred to as a “short” period.
what does right bending in actograms mean?
Right bending occurs when the activity onset or offset times of an organism’s circadian rhythm occur later each day compared to the previous day.
This can indicate a circadian rhythm with a period length slightly longer than 24 hours, often referred to as a “long” period.
what does no bending imply on actograms?
No bending occurs when the activity onset or offset times of an organism’s circadian rhythm remain relatively constant over time, without a noticeable trend towards earlier or later times each day.
This can indicate a circadian rhythm with a period length very close to 24 hours, often referred to as a “near-24-hour” period.
(right/left/no):
___ bending suggests that the organism’s internal clock is running slightly faster than the external 24-hour day, causing its activity rhythm to advance each day.
___ bending suggests that the organism’s internal clock is running slightly slower than the external 24-hour day, causing its activity rhythm to delay each day.
___ bending suggests that the organism’s internal clock is closely aligned with the external 24-hour day, with minimal daily drift in activity timing.
left; right; no
what is the circadian rhythm generator?
suprachiasmatic nucleus (SCN)
why is the SCN the circadian rhythm generator?
just above the optic chiasm bc the cue that entrains the clock to 24hr is light0> want to be close to the light transmission pathway
some optic fibers innervate the SCN (a subset of retinal ganglion cells directly innervate the SCN)
what is the step-by-step mechanism of the mammalian circadian clock?
- input pathways
- CLOCK-BMAL1 activation
- Transcription of Per and Cry
- Per/cry complex formation
- nuclear translocation
- inhibition of CLOCK-BMAL1
- degradation of per/cry
(8. additional regulation) - output pathways
what are the input pathways of the circadian clock?
The circadian clock receives input from environmental cues, primarily light-dark cycles, through specialized photoreceptor cells in the retina of the eye.
Light information is transmitted via the retinohypothalamic tract to the SCN, where it synchronizes the internal clock to the external day-night cycle.
what do CLOCK and BMAL1 do?
The primary positive elements of the mammalian circadian clock are two transcription factors, CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain and Muscle ARNT-like 1).
These proteins form a heterodimeric complex that binds to specific DNA sequences called E-boxes in the promoters of target genes, including Period (Per) and Cryptochrome (Cry) genes.
what are Per and Cry?
The Per and Cry genes are among the primary negative feedback elements in the circadian clock.
After transcription and translation, PER and CRY proteins form heterodimeric complexes and inhibit the activity of the CLOCK-BMAL1 complex.
This inhibitory action suppresses the expression of Per and Cry genes, creating a negative feedback loop.
what is the per/cry nuclear translocation?
The PER/CRY complex undergoes post-translational modifications and translocates into the nucleus.
Once inside the nucleus, it inhibits the transcriptional activity of CLOCK-BMAL1, thus repressing its own expression as well as that of other clock-controlled genes.
what are REV-ERB alpha and ROR alpha?
Another layer of regulation involves the nuclear receptors REV-ERBα (Reverse-erb alpha) and RORα (Retinoic acid receptor-related orphan receptor alpha).
These proteins compete for binding to ROR response elements (ROREs) in the Bmal1 promoter.
REV-ERBα represses Bmal1 transcription, while RORα activates it. This interplay between REV-ERBα and RORα provides additional regulation of the core clock machinery.
what are the output pathways of the circadian clock?
The circadian clock regulates downstream physiological processes and behaviors through output pathways involving clock-controlled genes.
These genes, whose expression is directly or indirectly regulated by the core clock components, mediate the circadian control of diverse cellular processes, including metabolism, hormone secretion, and sleep-wake cycles.
what does the locomotor activity rhythms of mice KO for BMAL1 gene look like?
disruption of bmal1 kills the clock
bmal1 the one and only component essential for the clock
need to take both per or both cry genes to get rid of the clock
(T/F): bmal1 the only one where single KO can disrupt the clock
true!
(T/F): the circadian clock is uninvolved in anticipation.
False!
why is the clock so complicated if light is sufficient to activate it?
photon flux:
- if 100 photons permits a single transcript to get to huge level, decay would be problem
- the clock provides a constant amplitude readout
has evolved bc of the clouds:
- regardless of rain or shine, independent on photon flux of LD cycle, circadian clock produces constatn readouts everyday regardless of how the whether is, rain or shine
what happens when Per protein is phosphorylated in certain sites?
it’s marked for degradation in proteosome pathways
so, per phosphoryalted-> per level drops (role of CKI)
what happens when CKI-e is mutated?
gain of function mutation
kinase more effective in phosphprylated its substrate-> per phosphorylated faster-> destabilized faster-> inhibition of their own transcription stopped faster-> can start new transcriptione arlier-> faster running clock
thus, inhibition shorter bc stability of inhibitor reduced
what is the Tau mutation in hamsters?
mutation of CKIε
less stable PER proteins (decreased duration
of inhibition of CLOCK/BMAL1)
hetero: 22h period; homo: 20h period
what do the actograms of Tau mutant hamsters show?
nice 24 hr activity in LD, but mutants under LD have mean shifted- extreme early birds
jump into running wheel way earlier than wt, couple hrs before lights off (nocturnal animal)
dramatically shifted -> prob competition between LD cycle and the endogenous faster clock
entrainment accomplished, but a different phase level
what are chronotypes?
morning-type and evening-type people (early bird and night owls)
dramatic distribution in the population
what are the 6 characteristics of advanced sleep phase disorder?
- Evening sleepiness
- Sleep onset earlier than desired (typically 4-6PM)
- Early morning awakenings (typically 1-4AM)
- Sleep recording generally normal (when performed at the patient’s desired sleep time)
- Generally in older individuals
- Some examples of familial ASPD
(T/F): in advanced sleep phase disorder, patients dont sleep the same amount
False: sleep architecture normal, total amount of sleep normal -> just a change in phase
what is familial advanced sleep phase disorder?
a mutation was found
in the genes encoding PER2 and CKI-tau (mutants in the same pathway)
– gain of function mutations = lead to speeding up of the clock
whats important to note in the differences of sleep onset and offset in affected vs non-affected family members?
sleep onset/offset in non-affected: “normal” (go to sleep at 11pm, wake up around 8am)
sleep onset/offset in affected: shifted (go to sleep at 7pm, wake up at 4am)
there’s a 3 hour difference in both sleep onset and offset
explain the study that looked at FASPD
put them in constant dim light conditions, no sense of time, food at random times, no way to know what time of day it is
measure sleep w polysomnography etc
CBT a good readout of circadian clock
bending toards he left-> shorter than 24 (this subject has 23h), way shorter than typical humans that have 24.1
(T/F): FASPD is analogous to Tau hamster.
true!
(T/F): being a night owl puts you at risk of any psychopathology.
true
what is the ultra-rapid (48hr) cycling in BD?
extreme example- 48hr
go to mania every second day and the second day later they are in depression
super regular
go into mania every decond day during entire recording epriod
case reports make cas that this regularity has persisted in these indviiduals for a decade
can schedule their appointments in advances based on knowing they’ll be in depression or in mania bc so regular
substantial number of reports out there, but is extremem cases
not exyremely rare but relatively rare
how does the 48hr-cycling extend to sleep in BP?
sleep follows exact same period
when in mania, sleep short (show sleep of 4hrs or something when in mania)
mood and sleep go hand in hand
(sleep diary onset/offset)
what did the polysomnography of the 48hr-cycling and sleep in BP show?
polysomnography
sleep architecture was normal even though they slept less
the 48hr cycling persisted even in constant dim-> endogenous-> not due to exogneous cues
constant conditions and no concept of time-> sleep cycling peristed
argues for endogenous origin of this cyclitiy
(T/F): Ultra-rapid cycling case reports have random cycling periods.
false: multiples of 24hr (i.e., cases of 48hr and 72 hr cycling)
explain the study on meth-induced rhythmicity frequency of 48hr periods
subject mice to methamphetamine (strongest psychostimulant) in drinking water, activity changes
see gradual right bending right hand side -> period becoming longer (very unusual, mice normally below 24) – as concentration increases, suddenly see that in addition to the 24 hr component, a second component emerges w a period much longer than 24 (the bigger peak)
a good fraction of the animals (not all) move to 48 hr cycling with increased meth concentration: left is second oscillatory component -> the 2 peaks come from 2 diff oscillator
first peak is circadian oscillator while the second peak is another oscillator coming on board through the treatment
but very diff feature- the oscilaltor is very tunable, period can vary dramatically
wherease the circadian clock is very rigid, can’t be tuned to very far from 24
what can we say for certain about meth-induced rhythmicity?
meth wakes up a second oscillator that has variable period
how does meth-amphetamine work?
acts on DAT- sets in in reverse
(all psychostimulants target DAT- either block it or set in reverse)
meth the most potent psychotimulant prob bc it sets it in reverse
meth-amphetamine treatment ___ extracellular dopamine
increases
why do we think that meth-based animal model is good to study 48hr cycling in BP?
looks strickingly similar to te mood thing
one day high activity, one day low in 48 hr cycle
-> think that these mice under meth are a good model of 48hr cycling in BPD
explain how the ablation of NAcc projecting DA neurons leads to second component loss
6 hydroxyldopamine kills DA neurons, but also kills DA neurons innervating the region where you inject
TH as marker of DA neurons (rate-limiting step for DA synthesis) -> drop in labelling in NAc
see effect of estrus cycle (more activity in proestrous stage in female mice)
response to meth gone
can’t produce this 48hr rhythmicity (no second component showing up)
side effect: activity lower
____ neurons drive Meth-dependent infradian rhythms in rest-activity including ___ rhythms
NAc projecting DA; 48hr
NAc-projecting DA neurons may serve as a substrate for _____
48hr cycling in BP
what were the results of the PAT study looking at DA in NAc of manic patients?
the diff was centralized to the NAc region
makes case the DAT tracer signal was lower in in that region, meaning more displacement of the radioactive tracer, which could mean more DA there to compete w the tracer
alternative is that DAT expression dropping
explain the DTI-MRI study in the BD patient with rapid cycling associated with her menstrual cycle
female bp cycling patient
on day 7 of menstrual cycle, would go into mania for 2 weeks, then 2 weeks of ehtemia (normal mood), then repeat itself w the next menstrual cycle
no skipping over a year, precisely cycling w menstrual cycle
more water molecular movement-> more neuronal activity
had no preconception of which brain areas to look at (pet tracer limits target to DA system)
here in mri, any region could come up, could be that a lot of differences would be observed
but the only places they observed differences was Nac and associated striatal regions
supports hypthesis NAc has major role in bpd at least in cycling patients
what is the dual-oscillator basis for mood cycling?
in menstrual cycle subjects
2 weeks mania, 2 eeks depression
very diff from 48
nut this mdoel can explain any cycle length
speed/periodnslighly linger than 24-> mania episodes would take some time before mania reached- might take 2 months, 2 years, 2 days
and the length of the mania depends on interaction w the circadian clock
the period long when not aligned but shortened slightly whn aligns w circadian bc circadian tries to make it alignsed, but eventually drigts away
beat cycling- 2 tones of slightly diff frequencies will have a woowoo output
beat cycling: if this oscillator align w circadian timer forever, you’re hypermotivated all day every day, don’t need to sleep a lot, think you’re the best
explain the study that looked at periodic sleep/activity drifting
subject w stereotypical time of sleep (midnight and 8 oclock)
then every fourth night or so, in complete opposite phase relationship
but it’s dirfiting slightly into it
oscilattor slowly travels out of the control of the circadian control
the mood follows exactly that behaviour
can of course say the circadian clock moves to antiphase, how can you say it’s the other oscillator
need to do more research to rule out the circadian clock producing this,that circadian stays aligned w LD cycle, and it’s really the other oscilaltor moving in and out
explain the study that looked at humans in temporal isolation
experiments in the 60s near munich created bunker to assess circadian timer in humans
to assess period of endogenous timer
concrete-surrounded, completely isolated
dim light; could switch on and off a little, but no bgiht light
no info about time
close to 100 subjects
controleld for various parameters, including CBT measured w a rectal probe
CBT a direct, invariable readout of CBT (a good phase marker)
reported circadian clock in humans a little longer than 24
this a quadruple plot of24
but see the actual circadian timer (CBT) stays at 24
but in about 20% of the subjects, dissociation of sleep witht he BDT
and looked like a diff sythmicity
very regular moving through
supportive of the idea that the 2 oscillators at play here, one circadian and onecontrolling sleep here
the subejcts were also reportign how they felt each day, quetionnaires, diary, etc
was found that the diay entries
when the 2 systems were coming into alignment, the diary entries said they felt particularly energetic and …
supports need to get alignment of the 2, motivated arousal (that’s what DA does)
what is the autography-based sleep recording and sleep-drifting/48hr cycling in BD patients?
at 2 or 1, then next day at 2:30, next day at 3:30, next day 4:30
reflection of the dopaminergic oscillator acting up
not consciously choosign to sleep 1 or 2 hrs later every day
sleep varies quite substantially between subjets based on actigraphy wirst recording (when move wrist less than 5 deg for 5 min, you sleep (80% accuracy))
what was the critique of the paper on actography/sleep-drifting and 48hr cycling?
was submitted to nature
one of the reviewers said remove any link to bpd bc in my experience as a clinican i have never seen this 48hr cycling
his argument would be the reason have not seen ot is bc when go to clinic, immediately treat w antipsychotic that masks it, and also don’t measure w actigraphy-> patient can’t tell you they
re drifting etc
he thinks eventually actigraphy will be a tool in the psych office
one might say they’re exhuasted and one says can’t sleep. but the actigraphy patterns opposite
might be too inactive wherease other patient too active
both exhausted but diff reasons (the two ones i highlihted)
what is the continuous wavelet transform scalogram?
Patients sorted by increasing energy in the infradian
range (27h-72h)
what are the antipsychotics effects on rest/activity in BP and the meth-based mouse model?
patient wanted to get off his antipsychotic that targets D2 receptor arapapipraxole
dialed the drug out then dialed it in
continued with his sleep recordings
the osllators drigted, became active, then normalized when givnen drug
ecactly same as in animals in lab – antipsychotric-> normalization
