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BMS381 Developmental Neurobiology > L14 - Sleep > Flashcards

L14 - Sleep Flashcards

1
Q

Define sleep-wake

A

Stable states that swtich due to a build-up of sleep pressure during wakefullness and dissipation of sleep pressure during sleep

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2
Q

Switch in states due to ….

A

Neurones that have antagonistic functions

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3
Q

What are the two classes of neruones involved in sleep

A

Wake promoting

Sleep promoting

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4
Q

Describe the wake promoting neurones

A

Activated by dissipating sleep pressure - promote the transiton to wakefullness

Found in various part of the brain

In hypothalamus - lateral hypothalamus and tuberomammillary nucleus

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5
Q

What activates sleep promoting neurones

A

Increasing sleep pressure -these promote the transition to sleep

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6
Q

ORexin AKA

A

Hypocretin

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7
Q

What region of the hypothalamus harbous hypocretin producing neruones?

A

Lateral hypothalamus

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8
Q

Where are neurones that synthesise and secrete histidine found?

A

Tuberomamillary nucleus

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9
Q

85-90% of narcoleptics …

A

Have a reduction in the number of hypocretin neurones

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10
Q

Narcolepsy

A

Strong link to HCr neurones and sleep
Chronic conditions causing drowsiness
Cataplexy and sleep paralysis common with this
Estimated to effect 1/2000 or 1/200000

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11
Q

What can cause narcolepsy

A

Lesions to TMN
Attack of TMN by viruses
Lack of histidine

MUTATIONS IN HYPOCRETIN LEAD TO NARCOLEPSY

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12
Q

What is the title of the paper used in sleep lecture

A

Evolutionary conserved regulation of hypocretin neruon specification by Lhx9

Liu 2015

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13
Q

Liu (sleep lecture) paper …

What model system was used

A

Zebrafish

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14
Q

Liu (sleep lecture) paper …

Why were ZF used

A

High throughput system to screen for factors that can specify Hcrt neurones in vivo

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15
Q

Liu (sleep lecture) paper …

TAKE HOME MESSAGE

A

Identified the LIM homeobox transcription factor Lhx9 as necessary and sufficient

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16
Q

Liu (sleep lecture) paper …

First steps

A

Make a transgenic reporter line

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17
Q

Liu (sleep lecture) paper …

Describe the reporter line made

A

RFP under the control of the Hcrt promoter

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18
Q

Liu (sleep lecture) paper …

How did they identify RFP+ cells

A

Use FACS to sort the dissociated cells for those expressing RFP

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19
Q

Liu (sleep lecture) paper …

What was special about the cells expressing RFP

A

RFP under control of the Hcrt promoter so Hcrt also transcribed in these cells

RFP+ cells ARE ALSO HCRT+ cells

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20
Q

Liu (sleep lecture) paper …

Results of the microarray analysis

A

One enriched transcript was lhx9`

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21
Q

What is eGFP

A

A stable form of GFP

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22
Q

Liu (sleep lecture) paper …

Results of in-situ on WT and transgenic line

A

Shows that all HCRT+ cells express Lhx9

23
Q

Liu (sleep lecture) paper …

Lhx9 _______ to specifity Hcrt neurones

A

Sufficiednt

24
Q

Liu (sleep lecture) paper …

How did they determine Lhx9 sufficient to specify Hcrt+

A

Grafted Lhx9 posotive cells into the reporter line

Observed floursecence at the site of injection

25
Liu (sleep lecture) paper ... What was the control to the experiment loking at sufficiency of Lhx9
Ectopic Hcrt+ neurones express markers than are normally detected in endogenous Hcrt neurones
26
Liu (sleep lecture) paper ... Second control experiement to show ectopic Hcrt neurones are true Hcrt neurones
Ectopic neurones also project to the same targets as the endogenous
27
Liu (sleep lecture) paper ... What were the conclusions from the control experiments of the ectopic grasftic of Lhx9 progenitors
Ectopic Hcrt+ neurones induced by Lhx9 are true hcrt+ neurones
28
Liu (sleep lecture) paper ... Lhx9 is required for
Hcrt neurones specification
29
Liu (sleep lecture) paper ... How was it tested to see if Lhx9 was required for Hcrt+ neurones
Used a splice blockign morpholino to knock down lhx9 expression Then did a knockdown using Cas9
30
Lhx9 ________________ hcrt expression Evidence 1 Evidence 2
DIRECTLY PROMOTES Double flour - In-situ agaisntly Lhx9 and Hccrt - Hcrt expression in all lhx9 overexpressing cells Lhx9 binding site upstream of another gene. See same bidning site upstream of Hcrt... Mutate the binding site... Lhx9 no longer activates transcription
31
Until recently we knew little of SLEEP PROMOTING neurones .... describe the recent discoveery
GABAergic neurones that develop under control of Lhx9
32
Wake promoting neurons cell types include
Hypocretin neruones of LH
33
Hypocretin neruones of LH promote
Transition from wakefullness to NREM and REM sleep
34
Gabaergic nerones which express Lhx9 activated by _________ Ibhibit Recieve inputs from
Sleep pressure Inhibit wake active hypocretin and GABAergic cells in the lateral hypothalamus and recieve inputs from multiple sleep-wake regulating neurones
35
Conditional deletion of Lhx9 from the developing diencephalon -->
Decreases in both NREM and REM
36
Liu paper 2 Sleep ... Describe the methods used
Lots of data to trace and study Lhx6+ nneruones - reporter line To show how behaviour is controlled - activate through optogenetics
37
Describe how hypocretins got their name ...
Luis de Lecea cDNA encoding the precurrsor of two putative neuropepties known since exp in hypothalamus and similar to secretin family termed HYPOCRETINS
38
Optogenetic studies of Hcrt neruones enabled discovery of what circuit
Hypocretin systems and locus coeruleus CRUCIAL TO SPONTANOUES WAKING
39
Describe the program development of Hcrt+ neurones
``` Shh+ hypothalamic floor plate like cells THEN Shh induces Lhx9+ progenitor cells (non-autonomous manner) THEN Lhx9+ progenitor cells THEN Lhx9 induces Hcrt+ neurons (autonomous) THEN Hcrt+ neurones ```
40
Is there a cure for narcolepsy
No cure
41
What drugs may be used to help with narcolepsy
AMPHETAMINES Help with day time sleepiness ANTIDEPRESSANTS Heps with supressing REM, cataplexy, paralysis and hallucinations HYPOCRETIN Helps cure dogs of cataplexy
42
How may cell replacement therapy used to treat narcolepsy
Use HCRT expressing neurones generatede
43
From Seifnejad et al paper (2019) Loss of HCRT (receptors or ligands)
Sleep disorder of narcolepsy with cataplexy in humans
44
From Seifnejad et al paper (2019) What were their methods
Sort and purify HCRT and MCH neurones from mouse hypothalamus RNA seq to determine factors of fate determination Loss of function
45
From Seifnejad et al paper (2019) Factors that determine Hcrt fate
``` Peg3 Ahr1 Six6 Nr2f2 Prrx1 ```
46
From Seifnejad et al paper (2019) Factors that determine MCH fate
Lmx1 Gbx22 Peg3
47
From Seifnejad et al paper (2019) Loss of Peg3, what about knockdown
Significant reduction of HCRT and MCH cell numbers Knockdown abolishes expression - two fold decrease in sleep duration
48
What was found nesc for HCRT production From Seifnejad et al paper (2019)
Ascorbic acid
49
From Seifnejad et al paper (2019) What was found nesc for MCH cell differentiation
BMP7
50
From Seifnejad et al paper (2019) What were the results which may exxplain the metabolic symtpoms of narcolepsy
Loss of Hcrt neurones in Hcrt-ataxin-3 mice leads to 50% decrease in expression in another orexigenic neuronpeptide QRFP
51
From Seifnejad et al paper (2019) Overview
Results provide a platofrm to understnad the development an expression of HCRt and MCH and their multiple funcctions in both health and disease
52
How is cell replacement therapy used
Take pluipotent stem cells and re program! Genetic reprogramming to alter the cell fate Culture cells Induce differentiation and implant back in
53
What are the clinical applications of iPSC cells
ability to differnetiaite into a number of cell types Vastly renewable Easily accessible Individual specific
54
iPSCs are individual specific - what does this mean?
They are personalised and so are non-immunogenic

BMS381 Developmental Neurobiology (16 decks)

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