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John Moubarek

on 9 August 2014

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Transcript of Optogenetics

Agenda for the Day
How does it work?
What can we do with it?
Path to Optogenetics
Idea was documented in 1999
- Possible future tools: "Ideal signal would be light...seems rather far fetched but it is conceivable..."
- Francis Crick
Using lasers directly on neurons
Chlamydomonas reinhardtii
Different opsins induce or inhibit synaptic activity

Channelrhodopsin-2 (ChR2)
Na+ influx when illuminated by blue light (470 nm)

Halorhodopsin (NpHR)
Cl- influx when illuminated by yellow light (580 nm)
ChR2 and NpHR
The Light gated Ion Channels
Opsins can be tolerated in the brain of living mammals without obvious impairments
Opsins can be transfected into mammalian cells
- Different wavelengths activate or inactivate neurons
Viral vectors to infect the target neurons
Can we insert these opsins into targets?
Viral genome is limited in size
limits the viral vectors’ packaging capacity
lowers specificity
limits the promoter’s expression levels
Some Problems
Retinal degeneration is the loss of photoreceptors- leads to complete blindness.

Can use optogenetics to create an “optical prosthetic”

Install channelrhodopsin-2 on the other intact cells of the retina (ON bipolar cells) and make them light sensitive

Restores the signals and center-surround organization of the ganglion cells

Mice can now see

Drugs will not work because there is nothing for the drug to bind to
Restoring Vision
Channelrhodopsin-2 (ChR2)
Halorhodopsin (NpHR)
According to World Health Organization, about 1 billion people are affected with neurological disorders.

Techniques of studying the brain
- Studying the behavior of brain damaged patients and determining the site of damage

- Measures the electrical activity of neurons

Unable to manipulate and study individual neural cells
Prior to Optogenetics
Functional Electrical Stimulation (FES)
- Small electrical pulses are applied to paralyzed muscles to stimulate movement
There is fatigue seen in patients
Correct recruitment
- Small to large
Turning muscles off
- Muscle spasticity with inhibitory opsins

Muscle Movement
A person’s will to act originates from the pre-frontal cortex, but what path?

Use projection to move backwards (brain stem on)

Discovered which cells are involved in motivation, even it moves from one brain region to another

Part of the brain stem, dorsal raphe nucleus is serotonin hub

Mice and challenges

Failure of these pathways stems depressions and other sever mental illnesses
Need motivation?
What did HM teach us?
- Hippocampus not needed for long term memory retrieval
Optogenetics revealed that was plan B
Mouse committed maze to memory
Inhibited just prior to maze = forgot
Inhibited 30 min prior to maze = remembered
HM was plan B

A Second look at HM
The Evolution of an Idea
The Simplest and Most Elegant Solution
What are the future possibilities?
Combination of optics and genetics to control events within specific cells of living tissue.

Allows scientists to control neural activity in response to colored light
A Light Switch for neurons
Inventing new tools to study the brain
Knew that there are different kinds of neurons in the brain

Needed to know how neural circuits work

To do this, needed to be able to drive activity OR silence activity of specific neurons
- Control the electrical activity
- Stretch activated channels
- Magnetic fields

Light driven ion pumps
Moving Drosophila proteins into cells
Custom built gated channels
Genomic mapping of the algae revealed this channel protein
Functions in neurons without addition of retinal
Poor penetration of light into deep tissues.
blood absorbs blue light
- Seizure, vision, neuromuscular, emotion, memory, etc
- Remote control legs for the paralyzed?
- Force plasticity for my next exam?
- Fearless soldiers?
- Remote control animals for spying?

Memory Trigger
Inhibit Hippocampus
Neural Pathway Ends
No Long Term Memory Retrieved
Memory Trigger
Absent Hippocampus
Neural Path straight to Cortex
Long Term Memory Retrieved
Inhibit Hippocampus 30 min prior
Memory Trigger
Neural path straight to Cortex
Long Term Memory Retrived
Memory Trigger
Plan A
Plan B
"Draw home"
Mice and Parkinson's
Genetically modify the animal to express the light sensitive channel
construct can be larger, expression of opsins is better
knock “in” the gene instead of implanting it, so that it will be expressed everywhere
“Red Shifting”
Engineer the opsins to be more sensitive to redder light
Possibility of exciting two genetically-distinct populations of neurons within the same brain site
Greater influx of ions
Narrow the wavelength sensitivity; make neurons sensitive to other wavelengths
•Movement Disorder in which the basal ganglia is affected
•Two pathways: Direct and Indirect Pathway
•Optogenetics in Mice: Control group, Direct and indirect pathway
•Parkinsonian mouse, restored movement

(Fork, Richard L. 1971)
(Zemelman et al.. 2002)
(Butler, James 2011)
(Buchen, Lizzie 2010)
(Llewellyn et all.. 2010)
The photocurrent opens the channel, the cell depolarizes, and an action potential occurs
The cell hyperpolarizes and inhibits neural activity
http:// www.youtube.com/watch?v=QA67v4vSg00
http:// www.youtube.com/watch?feature=player_embedded&v=GdRjdDW5_a0
http:// www.youtube.com/watch?feature=player_embedded&v=v7uRFVR9BPU
http:// www.youtube.com/watch?v=SbPcPzqV6aU
Full transcript