Circadian Rhythm Flashcards
circadian rhythm
biological rhythm with a 24hr period that persists in constant conditions
present in all organisms
benefit of the CR
survival advantage because organisms can anticipate rather than respond to environmental changes
CR functions
anticipates regular changes in the environment - tunes internal physiology to the external world
internal synchronisation (temporal organisation) - internal processes in different organs are coordinated
allow synchrony (temporal organisation) between species
examples of CRs
behavioural - sleep/wake, drinking, food
biological - glucose uptake, metabolic rate, alcohol degradation
physiological - bp, HR, pain threshold
amplitude
measures robustness of circadian period (highest to lowest period)
period
duration of one complete cycle in rhythmic variation
free running (tau)
rhythm free runs according to circadian clock H>24hrs mouse<24hrs
constant conditions, no external cues
entrainment
synchronisation of internal biological rhythms by external cues
zeitgeber
external cue
light is the primary zeitgeber
e.g. food intake/temperature
actogram
graph in CR research
vertical line = activity
exogenous vs endogenous daily rhythms
exogenous - response to change in environment by external/environmental rhythms (not internally generated)
endogenous - generated internally within the organism by a self-sustaining oscillator/biological clock (true CR)
what is the endogenous master clock
suprachiasmatic nucleus (SCN)
located at base of hypothalamus (above optic chiasm)
light perception
light detected by retina
impulses sent to SCN to entrain clock
rod and cones send signal to RGC via bipolar cells
how do RGCs detect light
melanopsin (opsin photopigment)
found in intrisically photosensitive RGCs (ipRGCs)
endoded by Opn4 gene
roles of melanopsin
light modulation of sleep
entrainment of CR
pupillary light reflex
exacerbates migraines
3 SCN inputs
1)input light pathway: retina-SCN via RHT
2)intergeniculate leaflet (IGL) innervation IGL-SCN conveys photic and non-photic info from dorsal raphe nucleus
3)DRN activated and MRN mediate entraining of arousal (non-photic)
role of CLOCK/BMAL1 heterodimers
produce Cry1/Cry2/Per1/Per2 genes in early circadian days - inhibited by nuclear accumulation of Per/Cry complex (late circadian days)
oscillatory feedback loop
core controlled genes (CCGs)
24 hrs to transcribe/translate genes - next cycle when Per/Cry degrades
rev-erb + per&cry
TF/represses Bmal1
negative regulator of Bmal1 (anti-phase to Per/cry) enhances core oscillations
mPer1 gene expression
highest expression during the mid circadian day (low proteins levels)
low mPer1 mRNA at the end of the circadian day (highest protein levels)
mPer1 mRNA expression occurs only when nuclear mPer1 protein cleared at the end of the circadian night
light entraining
RHT releases glutamate & PACAP
increases Ca2+ in SCN
activates MAPK/CaMK/PKA
CREB phosphorylation
Per regulation light resets cycle by increasing Per1/Per2 (clock genes)
hamster CR
> 24hrs
Tau mutant hamster has a shorter CR
Tau encodes protein kinase which phosphorylates Per1 and controls entry into nucleus
Casein Kinase I epsilon - degrades Per1/PTM of cry/per/changes length of TTFL/controls ability to go back to nucleus
in vitro CR monitoring
obtain single SCN neurons expressing bio-luminescence reporter gene per-1 luciferase
measure: individual cell oscillations and population
individuals SCN neurons retain CR activity and different period lengths (light up at different time) - cell-cell communication is important
structure of SCN neurons
shell: AVP/GABA
core: GRP/GABA/VIP
axon projects from core to shell, GABA is an activator and acts on shell, core synchronises shell, shell generates most SCN output, VIP excitatory action (binds VPAC2) like PACAP
VIP KO mice
Welsh et al., 2010
decreased transcription of per
desynchronised firing of SCN
weak behavioural rhythms
AVP mediated communication between SCN neurons
resistance to pertubation
AVP V1a-/V1b- normal CR but resistant to jet lag/ when L&D delayed = resynchronisation
AVP role = confers resistance to perturbation
which clock genes are present outside SCN
per/cry/bmal
otuside SCN
ovary and kidney
in vivo rhythm maintain by SCN signals/in vitro amplitude & precision declines
SCN is the master clock and slaves clocks in tissues
SCN communication with peripheral clocks
SCN entrains the peripheral clocks:
* hormonal signals - melatonin rhythms regulates CRs in pars tuberalis of pituitary
* cortisol/corticosteroid
* TSH
* Autonomic NS signals
* behavioural signals
* metabolic signals: restricted feeding can entrain liver enzyme rhythms
SCN output
subparaventricular zone (SPZ) - dSPZ controls body temp and projects to MPO region vSPZ relays to DMH (corticosteroid production)
dorsomedial hypothalamus (DMH) GABAergic to ventrolateral preoptic nucleus (VLPO) (arousal)
orexin neurons in lateral hypothalamus (LHA) - wakefulness and feeding
MCH neurons - GABAergic - active during sleep
melatonin
secreted by pineal gland - pinealocytes (which have a dense capillary network)
secreted during darkness (high in CSF/blood/saliva)
short t1/2 15-20 mins - fall at dawn/low during daytime
sends info about time of day to tissue which need it
humans - facilitates sleep and lowers body temperature
input pathway
PVN -multisynaptic pathway - superior cervical gangia in SC
sympathetic (adrenergic) fibres from SCG - innervate pineal gland
adrenergic fibres end in varicosities (no synapses) release NA close to pinealocytes (where sympathetic neuron fires)
light - SCN stimulation (GABA) - PVN inhibition - suppression of melatonin
melatonin location
SCN intensely in pars tuberalis of pituitary
melatonin onset - natural dim light
Receptors: DMH/VMH/MPO/PVTN/hippocampus
control of sleep
sleep = reduction of synaptic strength
controlled by 2 pathways: homeostatic/circadian
increased sleep = increased energy consumption duration
accumulation of metabolic byproduct - adenosine - activates sleep promoting neurons
caffeine blocks adenosine binding via R’s
wake vs sleep
waking = synaptic potentiation
sleep = synaptic downscaling, removes irrelavant info during memory consolidation/recovery of learning potential
synaptic proteins required for memory consolidation downregulated during sleep
sleep removes cellular by products
CSF diffuses into extracellular space to clear waste (sleep increases extracellular space by 60% vs 5% of sleep during awake
AB cleared 2x faster in sleep vs awake (Xie et al., 2013)
sleep improves both types of memory: declarative and non-declarative
cost of learning
increased energy consumption/signal:noise ration
reduced selectivity of firing
saturation of plasticity potential
nREM sleep
non REM sleep reactivates neural circuits implicated in information enco
hippocampus (temporary store/sharp wave ripples) to…
neocortex (long term store/slow wave oscillations)
thalamocortical spindles (coincide with slow wave prime neocortex for LT memory storage)
slow wave oscillations: synchronise spindles and sharp wave ripples/facilitates reactivation of hippocampal memories and redistribution to neocortex/allow plasticity at cortical synapses
circadian disruptors
change in period - high fat
change in phase - shift work
change in amplitude - night eating, insulin resistance
peripheral clocks: liver/muscle/fat/pancreas
when do rhythm disturbances occur
when clock is not synced with the environment
* shift work (outside 8am-6pm)
* jet lag
* old age
several days needed to resynchronise to new LD cycle (1day/1hr shift)
desynchronisation brings about: poor sleep/poor cognition/mood swings/GI probelms (risk of disease and cancer)
evidence of CR disturbances having an effect on health
increased risk of breast cancer in female shift workers and cabin staff for airlines
circadian disruption in carcinogenic
jones et al., 2019 - serial questionnaire (significant trend with number of hours per week but not night) (melatonin suppression/CR disruption?)
faster tumour growth in mice with disrupted CR
Filipski et al., 2004
mice injected with metastatic cells - tumour weight increased
decreased survival
timing of food intake contributes to weight gain
Arble et al., 2009
mice are nocturnal ~80% calorie intake at night
high fat food provided only during day/night
faster weight gain when food is consumed at the wrong circadian time (during day)
mutant animals with shorter circadian period (22hrs) under a 24hr light cycle
Martino et al., 2008
cardiac & renal disease when internal clock in SCN is in conflict with external environment - usually in shift workers
tau mutant (encodes Ck1e) affects TTFL - shorter endogenous period (22hr) in hamsters
tau under 24hrs: heart disease (cardiomyopathy/fibrosis/kidney disease/early death)
tau under 22 hrs: normal cardiac and renal structure and function
