Fixing faulty neural circuits Flashcards
What is channelrhodopsin selective for?
Cations (Na+, Ca2+, H+, K+)
What happens when channelrhodopsin opens?
The cell depolarises
How is channelrhodopsin activated?
What wavelength?
By blue light
460nm
How can expressing ChR in different brain areas do?
- Modify behaviour
- Help to recover the function of a specific brain area
What travels through halorhodopsin?
Chloride ions (Cl)
What is HR activated by?
What wavelength?
Yellow light
570nm
What happens when HR is activated?
Hyperpolarisation of the cell
What can HR be used in?
Correction in the circuitry when the brain is OVER EXCITABLE (eg. treatment for epilepsy)
What can be used to fix faulty neural circuits instead of ChR?
What is the structure of these compounds?
Small organic compounds
Structure - double bond and a part that binds to an ion channel
What happens when shine light onto the small organic compounds?
How?
Change the configuration of the compound from trans- to cis- configuration
By rotation around the double bond
How are small organic compounds administered when correcting faulty neural circuits?
They are injected into the eye or brain
What do the small organic molecules do in trans- configuration?
Cis-configuration?
Block the channel in trans- configuration
Don’t block the channel in cis- configuration
How do small organic molecules act on the target channels?
Which is more prolonged?
1) From the OUTSIDE of the membrane
2) From the INSIDE of the membrane - more prolonged as they don’t diffuse away
How do the small organic molecules act from the inside of the membrane?
They go through channels (TRPV1 or P2XR)
Are the methods of correcting neural circuits with ChR specfic?
HR?
Small organic molecules?
Non of them are very specific
Describe the photocontrol of GABA receptors
- Substitution of the part of a compound that binds to the ion channel with a LIGAND for the receptor
- The configuration of the compound can be changed using a specific wavelength of light
- In ONE configuration: ligand will bing and activate the channel
- In the OTHER configuration: ligand doesn’t activate the channel (ligand is AWAY from the binding site of the GABA receptor)
What happens when GABA receptors are activated?
What is this used for?
Hyperpolarisation of the membrane
Used to calm down the brain
How can photocontrol be used on other receptors?
What does the outcome depend upon?
Outcome depends on the channel and expression of the channel:
- AchR = hyperpolarisation
- Na channels = hyperpolarise
- Glutamate R = hyperpolarise or depolarise depending upon the glutamate channel and the cell
What can optical stimulation be used for?
To cure blindness
What is retinitis pigmentosa?
Where the visual field becomes smaller and smaller until the patient cannot see anything
What is the main cause of RP?
Photoreceptors dying - therefore no transduction
What drug can be used to stop photoreceptors from dying?
No drugs can be used to stop them dying
What can be used to reverse the effects of RP?
Artificial retina, containing:
- Light activated electrodes
- ChR
- HR
With an artificial retina, when is it best to stimulate the retina itself?
Mostly for retinitis pigmentosa
With an artificial retina, when is it best to stimulate the visual cortex?
When the optic nerve is damaged or not formed
Why is it important to activate as early as anatomically possible in the visual pathway?
Examples?
The further downstream in the pathway, the more difficult it becomes:
- Even at the level of the retina - large diversity of neurons that perform complex computations
- Different ganglion cells have different functions and project to different brain areas
When are motion sensitive retinal ganglion cells active?
Only when there is motion
What are the disadvantages of activating the artificial retina with electrodes?
How can this be overcome?
Disadvantages:
- Electrodes don’t survive for very long (tissue around the electrodes die with time)
- Have to stimulate ganglion cells or cortical cells with electrodes (other cells are more difficult) and these cells are very complex
Overcome by:
- Activating the artificial retina/visual cortex with ChR or HR
Why is it easier to activate ganglion cells than bipolar cells/photoreceptors using electrodes?
Ganglion cells face the inner eye
Bipolar cells and retinal cells are the other side of the tissue and are harder to get to
Why is it useless to stimulate retinal ganglion cells using electrodes?
Very complicated:
- Different types of ganglion cells (P-type, M-type) that respond to different stimuli
- Each ganglion cell also have centre-surround organisation of their receptive fields
- Also presence of direction selective cells
- Also have different responses to light in different colours
How do they cells in the cortex become even more complicated to stimulate using electrodes?
Hypercomplex cells
What is the optimal way to stimulate the retina to reconstruct the activity (before suffering with RP)?
Using light to stimulate the DEEPER layers of the retina:
- Bipolar cells
- Remaining photoreceptors
How can HR be used to reverse the effects of reinitis pigmentosa?
- Express halorhodopsin in the remains of the photoreceptors
- Illuminate with YELLOW light
- ON cells spike
- OFF cells stop spiking
Why is HR expressed in the remaining photoreceptors and not ChR?
Photoreceptors must HYPERPOLARISE in response to light
What is seen when the size of the yellow spot on the receptive field is increased? (When there is HR expressed)
- Increase in spike rate
- Until the yellow spot covers the whole of the receptive field, where the response of the ganglion cells gets smaller and smaller, until no activation
When HR is artificially expressed, what does moving yellow spots cause?
Activation of halorhodopsin:
- However, some cells respond to movement in one direction (preferred) more and the the other direction (null) less
What experiments show that everything past the photoreceptors is still intact?
What does this mean?
The same results are seen as would be in a normal retina when:
- Increase the spot of yellow light
- Use a moving spot of yellow light
Means if stimulate the remains of the photoreceptors - can restore vision to a very large extent
Why is stimulating the remains of the photoreceptors a disadvantage?
How can this be overcome?
The remains of the photoreceptors are also likely to degenerate
This can be overcome by:
- Expressing 2 different ion channels very close to the photoreceptors (in the dendrites of bipolar cells?)
OR
- Injecting small organic molecules into the eye
What ion channel is expressed next to ON cells?
ChR
What ion channel is expressed next to OFF cells?
HR
How are ChR/HR expressed in the dendrite of different bipolar cells?
Using specific promoters:
- Different for ON/OFF cells
What are the disadvantages of using small organic molecules?
Less specificity
What cells is it better the stimulate when trying to recover the function of the retina?
Why?
Bipolar cells
- Less complicated than ganglion cells
- Remaining photoreceptors are likely to continue to degenerate
