W12L2 - Gene, Brain, Behaviour

Question 1

What do optogenetics use to excite neurons by light?

Optogenetics: Light to control gene activity

Answer 1

Optogenetics uses microbial opsins (light sensitive molecules) to excite or inhibit neurons by light

• Each opsin responds to light of particular wavelengths
• Adeno-associated virus (AAV) is used to introduce microbial opsins (required genetic material)
  
  • Cell-specific promotor sequence can restrict opsin expression to particular cell type

Question 2

What responds to blue and yellow light respectively. What happens?

Answer 2

Blue Light

Channelrhodopsin-2 (ChR2) pump

• Allows positive ions into the cell
• Depolarization
• Neural excitation

Yellow light

Halorhodopsin (NpHR) pump

• Allows negative ions into the cell
• Hyperpolarization
• Neuronal inhibition

Question 3

How is light delivered in optogenetics. What is the key question?

Answer 3

• Light stimulating a particular rhodopsin is delivered through an implanted optic fibre
  
  • What behaviours are evoked or suppressed when particular cells are excited or inhibited?

Question 4

What happened to rats with stimulated chR2 in mouse amygdala cells

Answer 4

ChR2 - excitatory

Induced a predatory response

Question 5

What does an optogenetic system with CRISPR-Gas9 system allow?

Answer 5

• Light-controlled protein transcription
• Light-controlled genome editing

Question 6

From genes, to brain, to behaviour: What 2 aspects were discusssed?

Answer 6

1. ) Animal Models
2. ) Imaging Genetics

Question 7

What is bioinformatics and what is the advantage?

Answer 7

Genetic associations with behaviour can only hint at the biological pathways involved, unfortunately

• Bioinformatics
  
  • ‘Translate’ a human genetic mutation to target a homologous (similar) gene in a model organism
• Use model organisms for direct measurement at multiple levels
  
  • Structure
  • Function
  • Behaviour

Question 8

Which gene ecode serotonin? And where is the SNP of interest located?

Answer 8

• HTR1A is the human gene encoding the serotonin-1A receptor
  
  • The SNP rs6295 is in the promotor region of HTR1A, affecting protein transcription instead of structur

Question 9

Connecting genes to behaviour

Answer 9

• SNP rs6295 in the promotor region of HTR1A is associated with trait anxiety
  
  • Individuals with 1/2 copies of the G allele showed lower trait anxiety than individuals homozygous for C allele
    
    • GG/GC < CC

Question 10

Connecting genes to anatomy. (Includes how it does it)

Answer 10

• HTR1A SNP (rs6295) associated with serotonin-binding potential
  
  • Additional copies of the G allele were associated with increased binding potential
  • G allele impairs transcriptional repression of the promoter
    
    • Thereby, increasing expression of the 5-HT1A receptor

Question 11

How is binding potential measured

Answer 11

Positron emission tomography (PET)

• Detects radiation from an injected tracer with a high affinity for 5-HT1A receptors
• Measures binding potential, infer presence of serotonin-1A receptors
• Higher density of receptors leads to higher binding potential

Question 12

What kind of receptor is serotonin-1A?

Answer 12

• Autoreceptor
• Located at the presynaptic membrane, where it binds neurotransmitters released by the neuron
  
  • Regulates NT release

Question 13

Connecting anatomy to brain function

Answer 13

• Reduced capacity for regulation of 5-HT release is associated with increased amygdala reactivity
• Amygdala reactivity = Measured by comparing BOLD activation in the amygdala between two tasks
  
  • Matching angry or fearful faces vs. matching geometric shapes

Question 14

Connecting function to behaviour

Answer 14

• Increased amygdala reactivity is associated
  with increased trait anxiety
  
  • Amygdala reactivity was measured by comparing amygdala BOLD activation when viewing fearful vs. neutral faces

Question 15

Connect genes to function

Answer 15

• HTR1A SNP (rs6295) is associated with amygdala reactivity
  
  • Additional copies of the G allele were associated with decreased reactivity

Question 16

Connect anatomy to behaviour

Answer 16

Increased serotonin-binding potential throughout the brain is associated with lower anxiety

Question 17

Genes > Brain > Behaviour

Answer 17

Genes: rs6295 G allele (-) (+)

Brain Structure: 5-HT binding (low)(high)

Brain Function: Amygdala Reactivity (high)(low)

Behaviour: Trait Anxiety (high)(low)

Question 18

By comparing measurements across multiple levels, we can…

Answer 18

We can reveal the likely biological pathway linking a genetic variant to a behavioural phenotype

Question 19

Genes > Brain > Behaviour, explain the full process in terms of presence

Answer 19

• Presence of G allele of rs6295 impairs repression of HTR1A transcription
• Increased receptor density
  
  • indexed by binding potential
• Decreased amygdala reactivity
• Predisposes to low anxiety

Question 20

Genes > Brain > Behaviour, explain the full process in terms of absense

Answer 20

• Absence of the G allele of rs6295 promotes repression of HTR1A transcription
• Decreased receptor density,
  
  • indexed by binding potential
• Increased amygdala reactivity
• Predisposes to high anxiety