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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
K conductance symbol
G_K
26
When during the 24 hours the firing rate of neurones the highest?
During the day Hi Na leak conductanc gives a hi input resistance
27
Druing Day g_k g_NALCN Vm R_in
Decreased Increased Depolarised Increased
28
``` Druing Night g_k g_NALCN Vm R_in ```
Increased Decreased Hyperpolairised Decreased
29
In order for the clock to work properly what is needed How is this acheived
Synchrony Set of neurons in the SCN make and secrete a peptide - VASOACTIVE INTESTINAL PEPTIDE (VIP)
30
Lhx paper title
Lhx1 controls terminal differentiation and circadian function of the superchiasmatic nucelus
31
What is Lhx1
LIM homeodomain transcription factor
32
What is Lhx1 required for
Terminal differention of the SCN
33
Effect of Lhx1 deletion
loss of SCN-enriched neuropeptides involved in synchronisation and coupling to downstream oscillatorys among other aspects of circadian function.
34
Describe the closk in Lhx-1 deficient SCN
Dampened clock gene expression rhythms Rhythms are disorganised
35
Neurones from SCN form circuits with
OTHER HYPOTHALAMIC REGIONS PVN, Arc, VMH and LH
36
Why was there a link to mental health and the clock?
Because neruopsychiatric disease sufferers exhibit sleep and circadian rhythm disruption
37
Describe molecular differences in fibroblasts isolated from schizophrenic patiens
LOSS of rhythmicity in CRY and PER1 expression
38
Describe molecular differences in fibroblasts isolated from schizophrenic patiens WHAT IS SEEN IN PERIPHERAL BLOOD LEUKOCYTES
Decreased and disrupted diurnal expression of CLOCK, PER 1/2/3, CRY1 and a functional clock homologue NPAS2
39
Is changed to clock components a cause or a consequence
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
What paper linked clock defects and disease pathphysiology
Mouse models of clock mutants show manic behaviours implicating mechanistic and causal links between circadian clock and disease pathophysiology LANDGRAF ET AL 2007
41
What disease and circadian rhythms and genes controlling the moleuclar clokc involved in
Bipolar disorder
42
Methods of Landgraf et al
Stereotactically injected viral vesctors encoding shRNA to knockdown clock gene BMAL1 in the SCN
43
What was the main effect of Bmal1 knockdown on the clock
Circadian rhythms greatly attenuayed
44
What were the effect of BMAL1 knockdown mice in the helplessness paradigm
SCN-BMAL1-KD slower to escape Even before exposure to stress
45
What were the effect of BMAL1 knockdown mice in the tail suspension test
More time immobile
46
Conclusion of Langraf et al
Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioural despair and anxiety like behavour
47
The SCN-BMAL1-KD is a ....
New animal model of dpression
48
Who championed the idea that sleep and circ rhythm disfunction may be causal to mental illness
Russel Foster
49
Results of fosters study ...
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
Intrinsic clock evolved over millions of years to be in perfect synchony with light/dark clock Effect if the syncony is lost?
If synchrony lost then does it effect the hormonal physiological signals and health?
51
Most research on clock genes and MDD focusses on ... What may also play a sig role
CLOCK polymorphisms Lithium target GSK3
52
What is SAD
Seasonal affective disorder
53
What may contriubute to SAD
Circadian phase shift
54
What allelic combinations appear to increase risk of SAD
NPAS2 PER3 BMAL1
55
Genetic studies have found associations of chronic schizophrenia to what genes
CLOCK PER1 PER3 TIMELESS
56
What was the effect of Pregrnant F0 generation exposed to CCD stress
F0 - displayed depression like behaviours Produced F1 and F2 generation mice that exhibited mood associated behavioural phenotypes desipte a lack of stressers
57
Prental stress of the F0 correllated with
Elevation of plasma corticosterone levels in F1 mice
58
What was the effeect on the dinural expression profiles of circadian clock genes?
Disrupted in the SCN of F1 mice
59
Descurbe what proteomic revealed about the F1 mice
DISTINCT CHANGES IN PROTEIN EXPRESSION IN THE HYPOTHALAMUS Prorteins associated with cellular activities, metabolism, development and disease
60
Describe what the sex specific differences were??
Melanocortin 4 receptor expression was different in CCD F1
61
CCD
Chronic circadian disturbance
62
The paper concludes Maternal expusre to CDD during pregnancy can lead to ...
Sex specific mood disoerers that can persist for a least two generations
63
Clock genes may also be responsible for what otherer diseases
Metabolic syndrome Neurodegenerative diseases Immune systems diseases
64
How in melatonin under the control of clock genes
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
What is melatonin involved in
``` Circadian rhyth gene Sleep propensity Blood pressure regulation Immune function Detox of free radicals ```
66
Melatonin is a
POTENT ANTIOXIDANT
67
Why melatonin for therpaies
More efficient than other antioxidants
68
Why melatoinin importnant
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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