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1st Breaking Video IT_Pro 2017-05-24 Optogenetics 1 Optogenetics Consolato Sergi, M.D., Ph.D. University of Alberta Hospital 2017-05-24 Optogenetics 2 2nd Video - Optogenetics Optogenetics_ Controlling the brain with light? 2017-05-24 Optogenetics 3 Signals Single-electrode recordings - Limitations - Intracellular recordings: Only a few neurons and difficult in vivo - Extracellular recordings: No capture information about subthreshold activity, bias against small cells, poorly defined cell identities 2-deoxyglucose (2DG) imaging (H3 or C14) - Limitations - Visualization of active brain areas or neurons (post-mortem) - Temporal resolution in min or hrs, not msec. - ‘One-shot’ or ‘two-shot’ ways. PET/fMRI: poor spatio-temporal resolution, hemodynamic transformation, drug receptor activation patterns. Optical Intrinsic Signal Imaging (OISI): hemodynamic response in local capillaries related to local activity. Optogenetics (VSDI): membrane voltage, Voltage Sensitive Dye Imaging 2017-05-24 mostly sub-threshold activity in neurones and glia cells. 4 Optogenetics should allow fast depolarization / hyperpolarization of specific cells in living animals precise control and study of cell population dynamics the identification of causal positive and negative proof with cell specificity superior targeting & biocompatibility vs. electrical stimulation visual confirmation of target morphology using fluorescent labeling 2017-05-24 Optogenetics 5 Zhang F, Wang L-P, Boyden ES and Deisseroth K (2006) Channelrhodopsin-2 and optical control of excitable cells. Nature Methods 3(10): 785–792. Chlamydomonas reinhardtii- Wikipedia Channelrhodopsin-2 (ChR2) • Light-activated non-selective cation channel • Alga: Chlamydomonas reinhardtii • Requires all-trans retinal (ATR), which is present in mammals • 50 fS per channel -> 0.1–1M ChR2 molecules are required to achieve 1 nA 2017-05-24 Optogenetics 6 Zhang et al (2007) Multimodal fast optical interrogation of neural circuitry. Nature 446: 633– 641. Archaea – Wikipedia Halorhodopsin (NpHR) • Light-activated chloride pump • Archaebacterium Natronomas pharaonis • 22 mW/mm2 @ 560 +/- 27 nm • Inactivates after ~1 sec 2017-05-24 Optogenetics 7 Current Status of Applications Some published work in animals (e.g. mouse & zebrafish): • Control and mapping of the function of motor cortex • Expression restores light responses in retinal ganglion cells • Dissection of Parkinson’s circuitry • Dissection of role of DA neurons in behavioral conditioning • Temporally precise in vivo control of intracellular signaling • Potential control of epileptiform activity • High-speed mapping of synaptic connectivity • Dissection of a behavioral module in the spinal cord 2017-05-24 Optogenetics 8 Take Home Message Optogenetics is Nature Method of the Year 2010 and is going to have more biology applications in the future!!! ...but how much is there to be discovered? …is it up to us? More Information on Pub Med and on website of Dr. Chou Hung, Ph.D. vision.ym.edu.tw/courses/methods/Presenta tion2.ppt 2017-05-24 Thank you Optogenetics 9