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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
Q

Liu (sleep lecture) paper …

What was the control to the experiment loking at sufficiency of Lhx9

A

Ectopic Hcrt+ neurones express markers than are normally detected in endogenous Hcrt neurones

26
Q

Liu (sleep lecture) paper …

Second control experiement to show ectopic Hcrt neurones are true Hcrt neurones

A

Ectopic neurones also project to the same targets as the endogenous

27
Q

Liu (sleep lecture) paper …

What were the conclusions from the control experiments of the ectopic grasftic of Lhx9 progenitors

A

Ectopic Hcrt+ neurones induced by Lhx9 are true hcrt+ neurones

28
Q

Liu (sleep lecture) paper …

Lhx9 is required for

A

Hcrt neurones specification

29
Q

Liu (sleep lecture) paper …

How was it tested to see if Lhx9 was required for Hcrt+ neurones

A

Used a splice blockign morpholino to knock down lhx9 expression

Then did a knockdown using Cas9

30
Q

Lhx9 ________________ hcrt expression

Evidence 1

Evidence 2

A

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
Q

Until recently we knew little of SLEEP PROMOTING neurones …. describe the recent discoveery

A

GABAergic neurones that develop under control of Lhx9

32
Q

Wake promoting neurons cell types include

A

Hypocretin neruones of LH

33
Q

Hypocretin neruones of LH promote

A

Transition from wakefullness to NREM and REM sleep

34
Q

Gabaergic nerones which express Lhx9 activated by _________

Ibhibit

Recieve inputs from

A

Sleep pressure

Inhibit wake active hypocretin and GABAergic cells in the lateral hypothalamus and recieve inputs from multiple sleep-wake regulating neurones

35
Q

Conditional deletion of Lhx9 from the developing diencephalon –>

A

Decreases in both NREM and REM

36
Q

Liu paper 2 Sleep …

Describe the methods used

A

Lots of data to trace and study Lhx6+ nneruones - reporter line

To show how behaviour is controlled - activate through optogenetics

37
Q

Describe how hypocretins got their name …

A

Luis de Lecea

cDNA encoding the precurrsor of two putative neuropepties known since exp in hypothalamus and similar to secretin family termed HYPOCRETINS

38
Q

Optogenetic studies of Hcrt neruones enabled discovery of what circuit

A

Hypocretin systems and locus coeruleus

CRUCIAL TO SPONTANOUES WAKING

39
Q

Describe the program development of Hcrt+ neurones

A 
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
Q

Is there a cure for narcolepsy

A

No cure

41
Q

What drugs may be used to help with narcolepsy

A

AMPHETAMINES
Help with day time sleepiness

ANTIDEPRESSANTS
Heps with supressing REM, cataplexy, paralysis and hallucinations

HYPOCRETIN
Helps cure dogs of cataplexy

42
Q

How may cell replacement therapy used to treat narcolepsy

A

Use HCRT expressing neurones generatede

43
Q

From Seifnejad et al paper (2019)

Loss of HCRT (receptors or ligands)

A

Sleep disorder of narcolepsy with cataplexy in humans

44
Q

From Seifnejad et al paper (2019)

What were their methods

A

Sort and purify HCRT and MCH neurones from mouse hypothalamus

RNA seq to determine factors of fate determination

Loss of function

45
Q

From Seifnejad et al paper (2019)

Factors that determine Hcrt fate

A 
Peg3
Ahr1
Six6
Nr2f2
Prrx1
46
Q

From Seifnejad et al paper (2019)

Factors that determine MCH fate

A

Lmx1
Gbx22
Peg3

47
Q

From Seifnejad et al paper (2019)

Loss of Peg3, what about knockdown

A

Significant reduction of HCRT and MCH cell numbers

Knockdown abolishes expression - two fold decrease in sleep duration

48
Q

What was found nesc for HCRT production

From Seifnejad et al paper (2019)

A

Ascorbic acid

49
Q

From Seifnejad et al paper (2019)

What was found nesc for MCH cell differentiation

A

BMP7

50
Q

From Seifnejad et al paper (2019)

What were the results which may exxplain the metabolic symtpoms of narcolepsy

A

Loss of Hcrt neurones in Hcrt-ataxin-3 mice leads to 50% decrease in expression in another orexigenic neuronpeptide QRFP

51
Q

From Seifnejad et al paper (2019)

Overview

A

Results provide a platofrm to understnad the development an expression of HCRt and MCH and their multiple funcctions in both health and disease

52
Q

How is cell replacement therapy used

A

Take pluipotent stem cells and re program!

Genetic reprogramming to alter the cell fate
Culture cells
Induce differentiation and implant back in

53
Q

What are the clinical applications of iPSC cells

A

ability to differnetiaite into a number of cell types
Vastly renewable
Easily accessible
Individual specific

54
Q

iPSCs are individual specific - what does this mean?

A

They are personalised and so are non-immunogenic

BMS381 Developmental Neurobiology (16 decks)

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