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A BMS 381 - Developmental neurobiology > Olfactory mapping > Flashcards

Olfactory mapping Flashcards

1
Q

Where is olfactory information detected?

What receptors?

A

In the olfactory epithelium

By olfactory receptors

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2
Q

How many different olfactory receptors are there?

How many olfactory receptors does on neuron express?

A

1000s of different OR

One neuron expresses ONE TYPE of olfactory receptor

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3
Q

How are receptors organised in the nasal epithelium vs the olfactory bulb?

How does this change occur?

A

NE - dispersed
OB - organised

Occurs because neurons expressing one type of receptor go the the SAME glomerulus in the olfactory bulb

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4
Q

How is the mapping of the OE to the OB different to retinotectal mapping?

A

OE –> OB maintains DISCRETE information

RT - maintains TOPOLOGICAL information

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5
Q

How can the convergence of neurons to the OB be visualised?

A

Using Lac Z (reporter gene)

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6
Q

How use Lac Z to visualise convergence?

Why do it like this?

A

Use internal ribosome entry site:

  • Express more than one gene on a single mRNA transcript
  • Olfactory receptor and reporter share the SAMe RNA

So that the olfactory receptor ISN’T KO - can see the NORMAL BEHAVIOUR of the olfactory receptor

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7
Q

How are glomeruli arranged in the olfactory bulb?

A

Glomeruli responding to certain odours are CLUSTERED to particular part of the OB

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8
Q

What governs the guidance of olfactory neurons to the olfactory bulb?

How is this seen?

A

The receptor expressed (coding region)

Seen through receptor swap experiments

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9
Q

What is the structure of an olfactory receptor?

A

7 transmembrane pass GPCR-like molecules

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10
Q

What does OR activity determine?

How?

A

Guidance response state:

NO activation of OR (no ligand bound) –> first stage of guidance (to the olfactory bulb)

ACTIVATION of the OR (ligand bound) –> second stage of guidance (sorted into glomeruli)

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11
Q

How does early guidance TO the OB occur?

How are the axons sorted?

A

Activity-INDEPENDANT (no binding of ligand and no action potentials)

Sorted due to type I cue/receptor interactions

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12
Q

Describe the activity in of the OR in the ABSENCE of a ligand?

What causes this activity?

A

Each receptor - CHARACTERISTIC basal signalling activity

Caused by:
- Activation of adenylate cyclase and normal G protein activation and a specific level of cAMP

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13
Q

What determines the mapping to the olfactory bulb?

A
  • Specific levels of cAMP generated through adenylate cyclase activation
  • Via CREB, cAMP levels determine the level of type I molecules
  • This results in CHARACTERISTIC type I protein LEVEL being associated with the expression of a particular OR

(eg. when cAMP is low, Sema expression is high and Nrp level is low)
(eg. when cAMP is high, Sema expression is low and Nrp level is high)
- -> High level of receptor = repelled further away from axons expressing high level of repellant

  • LEVEL of type I molecule transcript in the axon forms a gradient on the way to the olfactory bulb which then drives a gradient in the OB

(Direct relationship between the level of transcript in the axon and the position along the DV axis in the OB

  • MAP emerges in the axons BEFORE they reach the OB (sort depending on the levels of type I molecule –> determines LEVELS of type I cue/receptor interactions)
  • LEVELS of type I cue/receptor determined by INITIAL RECEPTOR expressed –> determines point in gradient and therefore DV axis
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14
Q

What is CREB?

How does it activate different levels type I molecules?

A

cAMP response element binding protein (TF)

Activates different levels of type I molecules, dependant on the levels of cAMP
- In a GRADED way

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15
Q

What are type I molecules?

Examples?

A

Familiar guidance cues and their receptors

Robo/Slit
Neuropilin/Sema

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16
Q

What happens to mapping in the OB when guidance cue expression is disrupted?

A

Disrupts mapping

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17
Q

What happens to cue expression in the axons going to the OB over time?

Why?

A

Cue expression SWITCHES:

  • From Robo/Slit
  • To Nrp/Sema

So that EARLY entering axons can guide later entering axons

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18
Q

How are neurons sorted into the glomeruli?

A

ACTIVITY-DEPENDANT (action potentials):

  • Action potentials drive HIGHER cAMP LEVELS –> turns on expression of type II cues
  • Neurons expressing SAME adhesion molecule –> stick together and are REPELLED from ephs and ephrins
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19
Q

What happens to sorting into the glomeruli when block electrical activity?

A

Blocked

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20
Q

How can type II signals be used to sort neurons into the glomeruli?

A

In many different COMBINATIONS

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21
Q

What are type II molecules?

A

HOMOPHILLIC ADHESION MOLECULES (Kirrels and contactins (TAG1))

or

MUTUAL REPELLANTS (ephs and ephrins)

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22
Q

What is the ‘early’ sorting?

‘Late’ sorting?

A

Early:

  • Activity-independant
  • Pre-target sorting
  • Using Type I molecules

Late:

  • Activity-dependant
  • Glomerulus sorting
  • Using Type II molecules
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23
Q

Where do olfactory signals go after the olfactory bulb?

A

Relayed to HIGHER brain centres:

  • Piriform cortex
  • Amygdala
  • Olfactory tubercle
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24
Q

How are the projections from the OB to the piriform cortex different to projections from superior colliculus to LGN?

A 
OB --> PC = NO spatial organisation 
Mosaic organisation (individual odorants activate subpopulations of neurons DISTRIBUTED across the PC)
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25
Q

What cells output from the OB?

A

Mitral cells

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26
Q

What odorants do PC neurons respond to?

A

MULTIPLE, DISSIMILAR odorants

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27
Q

Describe the distribution of information from nasal epithelium to PC

A

Nasal epithelium - DISPERSED set of neurons activated

OB - Specific ensemble

PC - DISPERSED set of neurons

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28
Q

How does the brain know which odorant is which in a chaotic situation in the PC?

Describe this

A

ASSOCIATIVE LEARNING:

  • Odours drive behaviour AFTER LEARNING
  • Significance of odours is learnt by ASSOCIATION
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29
Q

How was it tested if the PC was the site of olfactory learning?

A

OPTOGENETICS:
- Introduce ‘channelrhodopsin’ (ChR2) into subset of PC neurons using tissue specific promoters

  • Stimulate ChR2 with light - activates PC without any input from mitral cells
  • Stimulate ChR+ subset of neurons with light and PAIR with either AVERSIVE of APPETITIVE stimulus in naive animals
  • Then, test is light alone can elicit the appropriate behavioural response
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30
Q

What is ChR2?

A

Light-activated CATION channel - produces action potentials under light

31
Q

What are ‘niave’ animals?

A

Animals that are unconditioned

32
Q

What are the 3 ways that ChR2 can be introduced into PC neurons?

A

1) Use SYNAPSIN PROMOTER injected into the cortex
2) Infect floxed ChR2 into mouse in which cre driven from Emx1 promoter (excitatory neuron-restricted)
3) Infect floxed ChR2 at the same time as the viruse containing synapsin driving cre

33
Q

Describe ‘using SYNAPSIN PROMOTER injected into the cortex’ to introduce Chr2 into PC neurons

A

Synapsin expressed in ALL neurons

Hits 50% of cells at the injection site

34
Q

‘Infect floxed ChR2 into mouse in which cre driven from Emx1 promoter’?

Process?

A

Hits 50% of cells but ONLY in EXCITATORY NEURONS

Cre lox sites used
Lox sites FACE each other in ‘flip’ orientation
Cre INVERTS the gene

35
Q

‘Infect floxed ChR2 at the same time as the viruse containing synapsin driving cre’

A

Work in ALL neurons

Much lower Chr2 expression rate (10%)

36
Q

How can ChR2 activation condition AVERSIVE behaviours? (experiment)

A

Photostimulation of ChR2-expressing neurons in PC (C stimulus) paired with FOOT-SHOCK (UC stimulus) on ONE side of the chamber

Animals then exhibited behaviour with PS alone

37
Q

What is an ‘unconditioned stimulus’?

A

A stimulus that naturally and normally evokes a response

38
Q

What is a ‘conditioned stimulus’?

A

Stimulus that is paired with an unconditioned stimulus, neutral and doesn’t normally provoke a response

39
Q

When using ChR2 activation to conditions aversive behaviours, when is the only time PS with elicit the response alone?

A

ONLY when ChR2 was present in the PC and a MINIMUM of 200 neurons transfected with ChR2

40
Q

What can conditioning odorants and PS together cause?

A

EITHER PS or ODORANTS can elicit flight

41
Q

How can ChR2 activation condition APPETITIVE behaviours? (experiment)

A

Mice trained to take water in response to odorant:
- Can be paired with PS or not

Male mice can be trained to associate presence of a female with either PS or odour

42
Q

How are the PC neurons plastic in their associative capacity?

A

The SAME set of ChR2-expressing PC neurons (in the same mouse) can be RETRAINED in either direction

DIFFERENT sets of ChR2-expressing neurons can be trained to have DIFFERENT behaviours

43
Q

Do the previous experiments prove that PC is the site of odorant learning?

What DO the experiments show?

A

NO, it just shows that PC can be used for associative learning (can happen here, but doesn’t mean it IS the site)

Shows that PC is very plastic - ANY group of 200 neurons can be used to elicit REVERSIBLE, DIVERSE behavioural responses

44
Q

Why is the PC plastic, whereas other regions of the cortex (eg. somatosensory) isnt?

A

Because the PC doesn’t have any spatial mapping, whereas the somatosensory cortex does (has a SPECIFIC behavioural out put according to location)

45
Q

What are random connections from the OB into the PC used for?

A

To ASSOCIATE odours with PARTICULAR EXPERIENCES (learned odours)

46
Q

How can it be tested if the PC is the site of associative learning?

A

LESION the PC and see if it works (get associative learning?)

47
Q

What are innate responses?

How are they triggered?

A

Inborn responses - happen without seeing a stimulus

Specific odours (eg. fox smell)

48
Q

Where are innate odours mapped to?

A

The AMYGDALA from the olfactory bulb

49
Q

Describe the mapping from the OB to the amygdala

Why?

A

Mapping is BIAST to particular regions from the OB

SPATIAL mapping to get FEAR response

50
Q

Can defects in axon guidance cause neurological disease?

A

Yes

51
Q

What is L1CAM?

A

L1 cell adhesion molecule (immunoglobulin-like) related to TAG-1 and NrCam

52
Q

What encodes L1CAM?

A

X-linked gene

53
Q

How does L1CAM adhese to things?

A

1) Bind homophillically

2) Bind to other UNRELATED cell adhesion molecules

54
Q

What are mutations in L1CAM associated with?

How is this known?

A

A broad spectrum of neurological disease:
- Hydrocephalus

  • Mental retardation (MASA syndrome)
  • Spastic paraplegia (SPG1)

Known through human mapping studies

55
Q

How is spastic paraplegia caused?

A

By faliure of the CSTs to project beyond the cervical regions

56
Q

What is L1CAM mutations characterised by?

How is this seen?

A

Defects in axon pathfinding at the pyramidal decussation of the CST

Seen by: KO of L1CAM and following the axons using a tracer

57
Q

What is HGPPS?

What are the symptoms?

A

Horizontal Gaze Palzy with Progressive Scoliosis:
- Monogenic disease

Symptoms:

  • Spinal twisting
  • Inability to control coordination between the 2 eyes (inability to control motor systems innervating the eye)
58
Q

What controls the motor systems that innervate the eye?

A

Pons and inferior olive

59
Q

What mutation causes HGPPS?

A
  • Mutations in Robo3 which normally inhibits robo1 as commisural axons cross the midline
  • No commissurless at the floor plate
60
Q

What commissures does HGPPS affect?

A

Several commissures (not just in the spinal cord)

Crossed fibre tracts in the pons that coordinate eye movement

61
Q

What do conditional KOs in HGPPS do?Why?

What does this show?

A

Mimics different aspects of the disease due to KO of different commissures

Shows coordination between different motor systems are disrupted

62
Q

What is the cause of scoliosis?

A

Not understood

63
Q

What is Kallmann’s syndrome?

A

Congenital anosmia (inability to smell) and hypogonadism (infertility)

64
Q

What causes Kallmann’s syndrome?

A

Mutations in several different genes:

  • Adhesion molecules (KAL1)
  • FGFR1 and FGF8
  • Sema 3A and Sema7A

Causes:
- GnRH (gonadotropin releasing hormone) neurons fail to migrate to the hypothalamus from the VNO (The vomeronasal organ - in the olfactory system)

  • Inability to regulate the development of the gonads to develop properly
65
Q

Why do mutations in Sema3A cause Killmann’s syndrome?

A

Sema3A is required for the olfactory epithelial axon guidance to the OB

  • NORMALLY, GnRH neurons migrate along these axons to the hypothalamus - SO, absence of OE axon guidance to the OB –> GnRH migrate to the wrong place
66
Q

Why do mutations in Sema7A cause Killmann’s syndrome?

A

Sema7A is required for GnRH neuron migration:

  • In absence, GnRH neurons FALL OFF OB axons projecting into the brain
67
Q

What is unusual about Sema7A use in GnRH migration?

How?

A

Acts as an attractant

Repellants can act as attractants in certain situations (PREVIOUS LECTURE)

68
Q

Describe the genetics of ASD, SZ, bipolar and depression

A
  • CLEAR genetic components (siblings likely to have the same condition)
  • COMPLEX genetics (NOT monogenic)
  • De novo copy number variations, mutations in multiple different genes
  • Lots of genes with low penetrance add up OR rare disease states add up
  • HUNDREDS of genes implicated
  • Overlap in the genetics of each disease type (many genes involved in one disease are involved in another)
69
Q

Describe the genetic risk factors for ASD, SZ, bipolar and depression

A

MANY genetic risk factors, EACH contributing to <1% risk

70
Q

What are examples of genes mutated in ASD, SZ, bipolar and depression?

A

Involved in:

  • Axon guidance
  • Synapse formation
  • Wnt signalling and polarity
  • Cell migration
71
Q

What is genetic redundancy?

What does it allow?

A

Biochemical function is encoded by 2 or more genes - compensation if there is a mutation

  • Allows the systems to function by pathway substitution
  • Allows to carry a lot of genetic damage/variation
72
Q

What may constitute to the wide variety of human ‘characters’ in the normal population?

A

The ability to survive well with many genetic and neurodevelopmental disturbances due to genetic redundancy

73
Q

What does variation between individuals mean (in regards to environmental insult)

A

Every individual is DIFFERENTIALLY vulnerable to environmental insult

74
Q

What are CST disruptions partly compensated by?

A

The RST (rubro-spinal tract)

A BMS 381 - Developmental neurobiology (17 decks)

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