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Systems Neuroscience > Circadian Rhythms, Photoreception And Sleep > Flashcards

Circadian Rhythms, Photoreception And Sleep Flashcards

1
Q

Circadian entrainment and free run

A

Entrained state - regular 24 hrs sleep wake cycle, body temp trough pattern near end of sleep
Free running - longer than 24 hrs but relative pattern but shifts slowly, body trough temp changes so onset of sleep
Entrained - reverts and trough drifts until reaches normal again

Conclude: synchronising impact of light and dark on sleep cycle and body temp, ~24 hr cycle so daily rhythms

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2
Q

Internal desynchronisation

A

Period length
Amplitude
Phase

Period length a lot longer so rhythms that usually are in the same period length with a fixed phase relationship relative to eachother now drift relative to eachother
So multiple time keeping sources in our body

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3
Q

Suprachiasmatic nucleus of the hypothalamus

A

Main site of central time keeper in brain
Contains molecular oscillators and synchronising intracellular peptidergic signalling (VIP, AVP)
Lesion of SCN abolishes circadian rhythms of physiology and behaviour
Disrupt expression of clock genes in SCN neurons abolishes rhythms
The SCN receives light input from retina

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4
Q

Light signalling

A

Light
Photoreceptors buried in ONL
Rods and cones signal to bipolar cells and then ganglion cells that collect into optic nerve
Pore arrangement so breaches light sensitive layer to leave the eye and go to brain

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5
Q

Vertebrate light signalling

A

Ciliary vertebrate photoreceptor rod or cone
Hyperpolerised so transmitting signals when there’s no light
Cation channels open so depol so higher rate of transmitter release in the dark

Light - cation channels close in response to redopsin and leads to hyperpol so drop in membrane potential

Glutamate signals to bipolar cells. Some bipolar cells are excitatory and some inhibitory
Dark - excitatory bipolar cells due to release of glu, glu in ganglion off cell and cause an action potential
Light - inhibitory bipolar cells due to disinhibition, release glu on ganglion on cells causing AP

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6
Q

Retinal ganglion cells and visual pathways

A

Info sent to visual cortex, superior caliculus for eye movement, dorsal lateral “connected” nuclei
Info from right eye goes to left side of brain and vice versa

Downstream of bipolar cells are ganglion cells and project laterally. Different types exist based on how they project

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7
Q

Retinal ganglion cells indirectly connect to pineal gland via SCN mediated pathway

A

Retinalhypothalamic tract (Glutermetergic) to SCN
Pathways to super cervical ganglion in brainstem or spinal cord
NA to pineal gland which produces melatonin in light inhibited manner (produced during dark)

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8
Q

Melatonin synthesis

A

Retina connects to SCN to PVN to upper thoracic cord the SCG that connect to the pineal gland via NA
NA bind to alpha and beta receptors on pineal sites which catalyse enzymatic reaction that turn tryptophan to serotonin to melatonin
Melatonin released into blood stream

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9
Q

Melatonin level measurement

A

Control group - high at night
Blue light - delay of melatonin next day, Acute effect direct loss of melatonin (intrinsically photosensitive retinal ganglion cells?)
Green light - delay of melatonin next day, Acute effect is delay (cones)

Light is a phase resetting cue
Eyes have blue light photoreceptors that don’t act in same way as green light photoreceptors

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10
Q

Visually bind sleep wake cycle

A

Both have 24 synchronised sleep wake cycle
Body temp rhythm synchronised in one individual and not in the other

Non 24 hr body temp - no ERG, no visually evoked potential, no pupillary reflex eg congenital glaucoma, would drift if not socially synchronised

24 hr body temp - no erg, abnormal vep, pr intact eg inherited mitochondrial optic neuropathies

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11
Q

Ciliary vs rhabdomeric pathways

A

Different secondary messengers
Ciliary hyperpolerises
Rhabdomeric depolarises

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12
Q

Ciliary pathway

A

Light on retina
Redopsin senses light that signals to G protein which activates cyclic GMP phosphodoesterase
Turns cyclic GMP to 5’ GMP so loss of cyclic GMP
Closing of CNG cation channels
So hyperpol

Negative feedback

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13
Q

Rhabdomeric pathway

A

Animals mainly
Redopsin senses light
GQ protein
Phospholipase c
Gating of cation channel (TRP) so depol as na+ and ca2+ in

Negative feedback

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14
Q

Vertebrate pigments include both ciliary and rhabdomeric opsins

A

Only a subset used for visual photoreception
In vertebrates - only ciliary opsins in visual photoreception

We have melanopsin in ganglion cells for non visual photoreception and is a rhabdomeric opsin

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15
Q

Circadian photoreception in mammals

A

Separable from vision but require the retina
Requires intrinsically photosensitive retinal ganglion cells which contain circadian blue light photipigment melanopsin, connect rods and cones to SCN and are selectively spared in mitochondrial optic neuropathies
Melanopsin act through rhabdomeric rather than ciliary pathway
Seasonal affective disorder associated with mutations in melanopsin gene

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16
Q

Melanopsin

A

Photopigment
Non image forming functions eg circadian rhythm

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17
Q

Melanopsin is expressed in a small number of retinal ganglion cells

A

Ganglion cell layer
Closer to inside of the eye than rod and cone cells

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18
Q

ipTGC projections

A

Connect to
OPN Olivary pretexts nucleus
d/vLGN dorsal/ventral lateral geniculate nucleus
IGL inter geniculate leaflet
SCN suprachiasmatic nucleus

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19
Q

Melanopsin impacts pupillary reflex

A

Mop -/- results in reduced pupillary reflex but not accent as other photoreceptors
Triple knock out plus knock out of rods and cones results in no pupillary reflex
Carbachol tests muscles ability to contract which it can do it is really signalling

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20
Q

Visual acuity

A

Ability to see individual grey and black lines
Eventually lose ability to see the lines based on frequency and contrast

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21
Q

Melanopsin supports pattern discrimination

A

Swim test of mice with platform based on ability to see patterns
Visual water test
No rods, cones or melanopsin then can’t do it
Melanopsin but not rods or cones they can still see some difference
So melanopsin dependent behaviour

Optokinetic tracking test
Watch mice head movement
No contribution of melanopsin

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22
Q

Melanopsin impacts light mediated circadian phase resetting

A

Light pulses of different strengths at night will shift its phase
Running on wheel

Melanopsin null still had phase resetting but reduced in level of phase resetting so sensitivity reduced

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23
Q

Melanopsin impacts circadian photoentrainment

A

All photoreceptors removed
Display innate period length not 24 hrs so shift in sleep wake cycle

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24
Q

Transgenic mice expressing receptor for diphtheria toxin in ipRGCs: selective ablation of ipRGCs by injection of diphtheria toxin

A

Instruct ipRGCs to commit suicide through expression of the toxin
So kill retinal ganglion cells
Visual cliff test, still good result
Pupillary reflex completely gone because photoreception not computed from both melonopsin or rods and cones
Act like in constant darkness all the time

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25
Q

Season affective disorder

A

3% in uk
Low mood, loss of pleasure/interest
Tiredness
Difficulty concentrating

Treatment with daylight/blue light
Most efficient wave length 470 nm
Post illumination pupil response to blue light is affected in SAD

SAD vs nondepressed (220 altogether)
SAD = 7 we’re homozygous for melanopsin P10L allele
5.6 x increased risk of SAD
Healthy have earlier bedtime in short days, later in long days

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26
Q

5 different types of ipRGCs

A

Projections
Response to stimulation (conductance)

M1 fast onset, slow offset, sensitive
M2-5 slow onset, slow offset, less sensitive

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27
Q

IpRGC Brn3b negative

A

M1 Brn3b negative
Projects to SCN
Rest circadian rhythm

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28
Q

m1 Brn3b positive and negative similarity

A

High melanopsin expression
Sensitive, fast onset, slow offset
Dendrites in OFF layer of IPL

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29
Q

Selective ablation of Brn3b+ ipRGCs

A

Only left with negative pathway
IpRGC > SCN projections mediate the impact of light/dark in learning and LTP
7 hr light 7 hr dark
Morris water maze
Novel object recognition
long term potentiation
Light pulse induction but not rhythmicity

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30
Q

The peri habenular thalamic area links non visual light input to mood

A

Elevates mood in light
T7 LD cycles impact
Sucrose preference test
Tail suspension tail
Forced swim test
Circadian rhythms in pHb
Dependent on Brn3b+ ipRGCs

But bilateral pHb inactivation takes away negative impact of t7 light/dark cycle
But activation of pHB makes mice depressed even in normal sleep wake cycle

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31
Q

SCN structure

A

Core - input from retina, VIP emntrainment function/synchronisation, melatonin, feedback from arousal centres, release GABA, VIP and GRP to shell part
Shell - pacemaker function, outputs GABA, AVP and PK2 to sPVZ and DMH resulting in secretion of molecules, arousal centres, neuro endocrine cells, pre autonomic neurons

32
Q

Molecular circuits of the circadian clock

A

Heterodimer of CLOCK & BMAL1(negative feedback loop by targeting BMAL)
Helix pas domain transcription factors
Bind to target sequence e box
Catalyses induction of many CLOCK control genes (CCGs)
Per1/2, cry1/2 have transcribed
Translated and assemble tripartite complex with kinases which phosphorylate per and cry components
Regulate stability and subcellular localisation
Once there’s enough, enters nucleus where per and cry inhibit BMAL CLOCK complex by binding to stop promoter binding

Time delay between transcription of period and cryptochrome and negative feedback on BMAL1CLOCK complex

33
Q

1994 - identification of circadian mutant mouse

A

Mutant called clock and result of large ENU screen for circadian mutants
Clock runs slow in this mutation

34
Q

Clock mutant

A

Lacks q rich activation domain
RNA Polymerase 2 cannot bind
51 aa deleted

35
Q

CLOCK interaction with BMAL1

A

BMAL looks like CLOCK but missing c terminal activation domain
So activation done by the complex is done by CLOCK
mutant clock = no activation domain so complex doesn’t work

36
Q

CLOCK and BMAL1 dimerise through PAS domains and bind to DNA promoter e-box

A

E box - CACGTG

37
Q

BMAL1 knockout nice are anything in DD

A

Light dark cycle can drive behaviour independently of BMAL1

38
Q

3 distinct per genes in mammals

A

Per 1,2 & 3
Per 1 and 2 knockout mice have aberrant rhythms
Per 3 knockout have good rhythms with slightly shorter periods

39
Q

Light indices mPer

A

Per 1 and 2 expression in the SCN
Phase of activity jumps if you give light pulses and then leave in darkeneds
Phase delay
Per 3 nearly no effect
Before CT 16 can get phase dealt
After CT 18 get phase advance

Per 1 and 2 are negative feedback molecules
Enhance in early night, alread inhibited BMAL so inhibition prolonged and delayed of phase

Late, ascending per 1 and 2 so advance because even more

40
Q

How do SCN get light info

A

Retinal hypothalamic tract
Axons of ipRCGs (M1 Brm3 negative)
Express glutamate and PACAP
Work on NMDAR, L type voltage gated sodium channels and PAC1R (AC or PLC)
CAMK from NMDAR and L type > CREB phosphate

PAC1R > AC or PLC > CREB phosphate
To resetting of circadian oscillator

41
Q

2 cryptochromes in mammals

A

One in drosophila - blue light photoreceptors
2 in mammals - transcriptional represses
Not athologues but homologues
Vertebrates don’t have drosophila cry
All came from DNA repair

All use pterin and flavin cofactors

42
Q

Both mCRYs are rhythmic in the SCN and retina

A

Protein level
Lights on no CRYs
2 hrs after lights off - CRYs detected with antibodies

Both mcry genes are rhythmically controlled by CLOCK/BMAL1

43
Q

Cytochrome knockouts cause alterations in period and/or arrhythmicity

A

Phenotype of circadian rhythmicity
Knock out both CRY 1 and 2 = arrhythmic mouse
Knockout CRY1 = fast running clock
Knockout CRY2 = slow running clock

So complementary functions and affects

44
Q

CRY proteins and PER proteins repress CLOCK/BMAL1 activation

A

Reporter assay in tissue culture cells
Measure: luciferase activity
Transferred with CLOCK & BMAL1 results in boost of expression
PER & CRY repress

45
Q

Tau mutant hamsters

A

NOT AD TAU
short and stable 22 hr cycle not 24
Bred and made homozygous for tau and now has 20 hr cycle
Hamsters don’t have convenient hamster, expensive etc

Point mutation of arginine to cysteine

46
Q

What does the tau mutation effect

A

May effect the catalytic site and substrate affinity

Homologise of fruity gene - double time
Authogue of double time is Casein kinase 1 epsilon and delta

47
Q

Casein kinase 1 epsilon binds and phosphorylates PER protein

A

Tau mutant shows normal binding but reduced in vitro kinase activity
Way more phosphorylation so weaker kinase

48
Q

Per1 mRNA rises earlier and falls earlier in tau mutant hamsters than wild type

A

Due to shortened period length

49
Q

Contrasting phenotypes of tau and CK1 epsilon null

A

Tau mutant qualitatively alters CK1 epsilon function
Knockout gene so period lengthened
Also CK1 delta in genome
Mutant and wild type counteract eachother

50
Q

Tau specifically destabilises PER 1/2 protein

A

MRNA relatively unaffected
Accumulation ok but nuclear clearance of PER protein accelerated in tau mutant

51
Q

Tau summary

A

Altered substrate specificity to PER1/2
Destabilise sites phosphorylated
Stabilising sites targeted less and so accelerated nuclear clearance

52
Q

Familial advanced phase sleep syndrome

A

Advance of 4-6 hrs relative to controls
Single gene trait
Mutation in hper2
Point mutation in PER2 gene at site phosphorylated by Caseinkinase1 epsilon
Serine changed to glycine (S662G)
Fast running clock also seen in flies

Deficient phosphorylation of hPER2

53
Q

Mutant analysis in mouse PER2

A

Cellular clocks show the FASPS phenotype
Expression of FASPS or mut7 PER2 in tissue culture results in reduced stability and early nuclerat clearance (through cychloeximide which is an inhibitor of translation)

54
Q

FASPS in summary

A

Mutated phosphorylation sites in FASPS destabilises PER2 protein and advanced nuclear clearing
Resembles tau mutant and tau kinase shows specifically reduced activity for FASPS site
Another FASPS pedigree identified T44A mutation in casein kinase 1 epsilon which reduced kinase activity

55
Q

Interlocked loop leading to rhythmic expression of BMAL1

A

BMAL1 rhythmically expressed under control of RORs and REV-ERBs (REVs negative regulators, RORs positive regulators)
E box controlled so simultaneously expressed with PERs and CRYs

REV-ERBs dominant so repress expression of BMAL1 so ends up out of phase
REV-ERBs turned over RORs take over and so out of phase of PER and CRY etc

56
Q

Sleep controlled by clock and homeostat

A

Build up sleep debt when awake
Pay back sleep debt when asleep
Circadian cycle coincides

57
Q

What is sleep

A

Altered consciousness
Reduced movement and responsiveness
Change Typical posture
Homeostatic regulation
Daily rhythmicity
Loss of muscle tone
Rapid eye movements in REM

58
Q

Measure sleep through electrode (Electroencephalogram)

A

High frequency low amplitude = wake and REM sleep
High amplitude low frequency = non REM sleep

59
Q

Electroencephalogram

A

Neurons not synchronised not much pattern
Synchronised then waves seen

60
Q

EEG during 1st hr of sleep

A

Progress to higher amplitude lower frequency waves
Awake beta waves
Stage 1 theta waves
Stage 2 theta waves
Stage 3 theta waves
Stage 4 delta waves
Then REM sleep

61
Q

NREM sleep

A

Reduced physiological activity
Shift to parasympathetic activity
Thermoregulation maintained

62
Q

Sleep cycle

A

REM periods 90-120
First REM period shortest
Most REM sleep occurs late
Most deep sleep (stage 3,4) early

With age
Similar amount of REM sleep
Diminishing 3,4 sleep
Increased sleep fragmentation

63
Q

Polysomnogram of REM sleep

A

Heart rate, respiration, EEG, neck muscles, penile responses

Resembles wake state for brain activity, heart rate, respiration

Diverges for
Eye movement, muscle tone, thermoregulation, penile erection

64
Q

Suppression of somatosensory response and muscle relaxation during REM sleep

A

Inhibition of cells in dorsal column nuclei results in diminished response to somatic sensory stimuli resulting in inhibition of lower motor neurone and so paralysis
Glu, 5HT and ACh All inhibited by GABA

65
Q

Brain areas responding to wake

A

Tubero- mammillary nucleus of hypothalamus (TMN) - histolergic
Locus coeruleus- NE
Raphe nuclei - 5HT
Cholinergic nuclei - ACh
Lateral hypothalamic area - orexin

66
Q

Brain regions responding to NREM

A

Ventrolateral preoptic nucleus (VLPO) - GABA
sciences other NTs relating to wake

67
Q

Brain regions responding to REM

A

VLPO - GABA
LDT - ACh
PPT - ACh

68
Q

Why do we need sleep

A

Sleep is necessary
Skin lesions
Swelling of paws
Loss of motor control
Loss of EEG amplitude
Stomach ulcers
Respiratory symptoms

69
Q

Cognitive impact on sleep disruption

A

Innattention
Changes in cortical EEG responses
Slower computational speed
Impaired verbal fluency
Reduced creativity
Reduced abstract problem solving
Learning issues
Lower IQ

70
Q

Theory: clean toxins out of brain

A

Sleep triggers increased drainage of the brain
AB peptides flushes more during sleep

71
Q

Theory: sleep unclutters the brain

A

Eliminate unnecessary connections
Challenge connections and those connected to pre existing circuits survive
Dendritic spines reduced (seen experimentally)

72
Q

Synaptic homeostasis hypothesis

A

Sleep improves cognitive ability
Synapses strengthen during wake
Spontaneous firing during sleep weakens synapses selectively Eg Limits energy use, remove unnecessary info, restore memory/ learning capacity, limit cellular resources

73
Q

Experimental evidence for synaptic homeostasis hypothesis

A

No. Of dendritic spines and axon spine interface increase during wake and decreases during sleep (mice and flies)
Evoked responses are lowered during sleep (electricity and mice)
AMPA glu receptors increase during wake but decrease during sleep (as well as others)
NREM sleep slow waves decrease in course of sleep
NTs and BDNF concentrations lower during NREM
Local NREM strength determined by plasticity use during wake “local sleep” during sleep deprivation
Important during brain development

74
Q

How does synaptic homeostasis hypothesis work

A

Post synaptic protein, Homer, in many forms
Tetrameric form - link metabolic glu receptors to calcium channels in er and activation
Truncated version - sleep, evh domain and (coiled coil produced) , can’t make connection in postsynaptic density so less active state of neurons

Homer 1A just EVH
Homer long EVH and coiled coil
Tetrameric form big

75
Q

Sleep

A

Increased 1A in post synaptic density
Decrease mGlu-R signalling
Arc May impact AMPAR similarly
Synaptic weakening via GSK-3 beta
Inactivated at S9 during wake

76
Q

Criticism if synaptic homeostasis hypothesis

A

Mechanisms not clear
LTP during NREN in model of monocular deprivation
Some arguements are species specific
Other rational possible eg drainage of toxins via lymph like system, selective growth of glia
Role of REM sleep?

Systems Neuroscience (5 decks)

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