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BMS381 Developmental Neurobiology > L15 - Circadian Cycles > Flashcards

L15 - Circadian Cycles Flashcards

1
Q

___ rhytms in physiology and behaviour generated by _______

A

24

Molecular clocks

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2
Q

What is the function of the molecular clocks

A

Coordinate internal time with the external time

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3
Q

The circadian clock serves to

A

Anticipate the regular 24 hours to ensure phys and behav outputs are appropriate time window each day

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4
Q

Most cells with a molecular clock maintained in _____ with a ___________ in the ______________

A

Synchrony
Master Clock

SUPER CHIASMATIC NUCLEUS

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5
Q

What percentage of the transcriptome displays a circadian rhythm

A

Between 2 and 30%

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6
Q

Core biological processes are under

A

Control of clock genes

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7
Q

what studies in what system have allowed us to learn the most about how the clock is biologically embedded

A

Molecular studies

In Drosophila

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8
Q

What is esentailly the mechanism of clock

A

Cell autonomous transcription and translation feedback loops

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9
Q

What are the two TFs involved in the circadian clock

A

CLOCK

BMAL1

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10
Q

CLOCK and BMAL1 drive expression of

A

Period (Per1/2)

Crytochrome (Cry1/2)

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11
Q

What is the effect of Per1/2 and Cry1/2

A

PROTEIN PRODUCTS feed-back by inhibiting CLOCK and BMAL1

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12
Q

Once Per1/2 and Cry1/2 have inhibited BMAL1 and CLOCK what happens to
them

THEN

A

They are degraed

THEN

BMAL1 and CLOCK build up again

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13
Q

Mechanism of the circadian clock takes how long

A

24 hours

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14
Q

What can input to the clock

A

Environmental cues

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15
Q

Give an example of an environmental input to the clock

A

Light acticivates Cry gene and promotes it bidning to TIM

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16
Q

What is the effect of cry binding to TIM

A

Prevents expression of Cyc

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17
Q

What studies have helped us to understant to make up of the clock

A

Gain and loss of function studies

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18
Q

Describe how it can be seen that SCN neurones are competent, cell autonomous circadian paceamkers

A

Micrographs of cultuered SCN neruones

Record PER2 expression using a bioluminescent reporter of per2 abundance levels

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19
Q

What was seen when using a marker for PER2 abundance in cultered SCN neurones

A

Persistent dailty rhythms

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20
Q

Describe the molecular drivers of the circadian clock in SCN neirones

A

EACH NEURONE HAS AN INSTRINSIC CAPACITY TO GEN DAILY OSCIATIONS

During day - UP STATE
Na leak conductance increase, K conductance decreases so increased input res, more depolarised Vm - higher firing rate

During night - DOWN STATE
Na leak decrease, K conduct increases, lower res, hyperpolaised Vm - lowerer firing day

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21
Q

Excitatory drive of Na currents during day …

A

Opposed by elevated K currents at night

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22
Q

During day neurones in …

A

Up state

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23
Q

During night neurones in …

A

Down state

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24
Q

Na leak condutance symbol

A

g_NALCN

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25
Q

K conductance symbol

A

G_K

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26
Q

When during the 24 hours the firing rate of neurones the highest?

A

During the day

Hi Na leak conductanc gives a hi input resistance

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27
Q

Druing Day

g_k
g_NALCN
Vm
R_in

A

Decreased
Increased

Depolarised
Increased

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28
Q 
Druing Night
g_k
g_NALCN
Vm
R_in
A

Increased
Decreased

Hyperpolairised
Decreased

29
Q

In order for the clock to work properly what is needed

How is this acheived

A

Synchrony

Set of neurons in the SCN make and secrete a peptide - VASOACTIVE INTESTINAL PEPTIDE (VIP)

30
Q

Lhx paper title

A

Lhx1 controls terminal differentiation and circadian function of the superchiasmatic nucelus

31
Q

What is Lhx1

A

LIM homeodomain transcription factor

32
Q

What is Lhx1 required for

A

Terminal differention of the SCN

33
Q

Effect of Lhx1 deletion

A

loss of SCN-enriched neuropeptides involved in synchronisation and coupling to downstream oscillatorys among other aspects of circadian function.

34
Q

Describe the closk in Lhx-1 deficient SCN

A

Dampened clock gene expression rhythms

Rhythms are disorganised

35
Q

Neurones from SCN form circuits with

A

OTHER HYPOTHALAMIC REGIONS

PVN, Arc, VMH and LH

36
Q

Why was there a link to mental health and the clock?

A

Because neruopsychiatric disease sufferers exhibit sleep and circadian rhythm disruption

37
Q

Describe molecular differences in fibroblasts isolated from schizophrenic patiens

A

LOSS of rhythmicity in CRY and PER1 expression

38
Q

Describe molecular differences in fibroblasts isolated from schizophrenic patiens

WHAT IS SEEN IN PERIPHERAL BLOOD LEUKOCYTES

A

Decreased and disrupted diurnal expression of CLOCK, PER 1/2/3, CRY1 and a functional clock homologue NPAS2

39
Q

Is changed to clock components a cause or a consequence

A

Disruption of molecular clock is not just a consequence by forms part of a bidrectional feedback loop with neruopsychiatric disease where pertubations one exacerbate dysfunction in the other

40
Q

What paper linked clock defects and disease pathphysiology

A

Mouse models of clock mutants show manic behaviours implicating mechanistic and causal links between circadian clock and disease pathophysiology

LANDGRAF ET AL 2007

41
Q

What disease and circadian rhythms and genes controlling the moleuclar clokc involved in

A

Bipolar disorder

42
Q

Methods of Landgraf et al

A

Stereotactically injected viral vesctors encoding shRNA to knockdown clock gene BMAL1 in the SCN

43
Q

What was the main effect of Bmal1 knockdown on the clock

A

Circadian rhythms greatly attenuayed

44
Q

What were the effect of BMAL1 knockdown mice in the helplessness paradigm

A

SCN-BMAL1-KD slower to escape

Even before exposure to stress

45
Q

What were the effect of BMAL1 knockdown mice in the tail suspension test

A

More time immobile

46
Q

Conclusion of Langraf et al

A

Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioural despair and anxiety like behavour

47
Q

The SCN-BMAL1-KD is a ….

A

New animal model of dpression

48
Q

Who championed the idea that sleep and circ rhythm disfunction may be causal to mental illness

A

Russel Foster

49
Q

Results of fosters study …

A

Signigicant sleep disturbance in all participants with Scizophrenia

HALF - showed severe circadian misalignment ranging from phase-advance/delay to non-24h periods in sleep wake and malatonin cycle

HALF - patterns of excessive sleep to highly irregular and fragmented sleep epochs but with normally timed melatonin production

50
Q

Intrinsic clock evolved over millions of years to be in perfect synchony with light/dark clock

Effect if the syncony is lost?

A

If synchrony lost then does it effect the hormonal physiological signals and health?

51
Q

Most research on clock genes and MDD focusses on …

What may also play a sig role

A

CLOCK polymorphisms

Lithium target GSK3

52
Q

What is SAD

A

Seasonal affective disorder

53
Q

What may contriubute to SAD

A

Circadian phase shift

54
Q

What allelic combinations appear to increase risk of SAD

A

NPAS2
PER3
BMAL1

55
Q

Genetic studies have found associations of chronic schizophrenia to what genes

A

CLOCK PER1 PER3 TIMELESS

56
Q

What was the effect of Pregrnant F0 generation exposed to CCD stress

A

F0 - displayed depression like behaviours

Produced F1 and F2 generation mice that exhibited mood associated behavioural phenotypes desipte a lack of stressers

57
Q

Prental stress of the F0 correllated with

A

Elevation of plasma corticosterone levels in F1 mice

58
Q

What was the effeect on the dinural expression profiles of circadian clock genes?

A

Disrupted in the SCN of F1 mice

59
Q

Descurbe what proteomic revealed about the F1 mice

A

DISTINCT CHANGES IN PROTEIN EXPRESSION IN THE HYPOTHALAMUS

Prorteins associated with cellular activities, metabolism, development and disease

60
Q

Describe what the sex specific differences were??

A

Melanocortin 4 receptor expression was different in CCD F1

61
Q

CCD

A

Chronic circadian disturbance

62
Q

The paper concludes

Maternal expusre to CDD during pregnancy can lead to …

A

Sex specific mood disoerers that can persist for a least two generations

63
Q

Clock genes may also be responsible for what otherer diseases

A

Metabolic syndrome
Neurodegenerative diseases
Immune systems diseases

64
Q

How in melatonin under the control of clock genes

A

Produced in the pineal gland with a circadain rhythm

Low during day, high at night

Pineal regulation is through the master clock in the SCN

65
Q

What is melatonin involved in

A 
Circadian rhyth gene
Sleep propensity 
Blood pressure regulation 
Immune function 
Detox of free radicals
66
Q

Melatonin is a

A

POTENT ANTIOXIDANT

67
Q

Why melatonin for therpaies

A

More efficient than other antioxidants

68
Q

Why melatoinin importnant

A

animal models suggest it is critical to clear free radicals and that failure to do so can cause mental health and neurodegenerative diseases

BMS381 Developmental Neurobiology (16 decks)

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