Optogenetic studies of brain disease : engineering light delivery into biological tissue
- Murtaza Mogri.
- June 2011.
- Physical description
- online resource (xiv, 109 pages) : illustrations (some color)
- Mogri, Murtaza.
- Deisseroth, Karl thesis advisor (primary).
- Graves, Edward (Edward Elliot), 1974- thesis advisor.
- Henderson, Jaime (Jaimie M.). thesis advisor.
- Palanker, Daniel thesis advisor.
- Shenoy, Krishna V. (Krishna Vaughn). thesis advisor.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Stanford University. Department of Bioengineering.
- Includes bibliographical references (p. 101-109).
- Optogenetic neuromodulation is giving scientists an unprecedented ability to modulate neural circuits, providing specificity with regards to location, cell type, as well as neuromodulatory effect. On the other hand, electrical stimulation and lesions, methods commonly used to study neural circuits, are lacking in specificity, often affecting both local cells and passing axons, as well as multiple cell types. Our laboratory has been at the forefront of the field of optogenetics, having developed, for use in mammalian systems, Channelrhodopsin-2 (ChR2), an algal light-activated cation channel that depolarizes neurons in response to blue light, and Natronomonas pharaonis halorhodopsin (eNpHR), a chloride pump that hyperpolarizes neurons in response to amber light. These proteins can control neuronal activity with millisecond timescale precision, and through promoters, they can be targeted to specific cell-types in heterogeneous tissue. Along with its specificity, light stimulation with optogenetic tools often allows the recording of neural activity without the artifact that obfuscates recordings with electrical stimulation. The advantages provided by optogenetics allowed us to make a breakthrough in determining the therapeutic mechanism of deep brain stimulation, a robust treatment for Parkinson's disease in which stimulating electrodes are implanted deep in the brain. Using optogenetics, we replicated the effect of deep brain stimulation by modulating cortical inputs into the region where the stimulating electrode is normally placed. Combined with other corroborating publications, a hypothesis is emerging that electrical stimulation deep in the brain actually produces its effect by modulating cortical projections to the deep brain region. Based on this concept, several clinical studies are being done to better understand the cortical role in Parkinson's disease and determine whether cortical stimulation (potentially non-invasive), could be an alternative to the invasive implants currently used. In order to perform these experiments, we studied the transmission of visible light in brain tissue to estimate the volume of activation produced by optogenetic stimulation and developed a device to measure fluorescence in awake, behaving animals, allowing the quantification of virally transfected gene expression over time, as well as the localization of expression along axon bundles. The knowledge gained from these experiments will have a significant impact on future experiments in the broader field of optogenetics.
- Axons > physiology
- Optogenetics > methods
- Parkinsonian Disorders > physiopathology
- Brain Diseases
- Halorhodopsins > metabolism
- Motor Cortex > pathology
- Rhodopsin > metabolism
- Local subject
- Biomedical Engineering
- Publication date
- Submitted to the Department of Bioengineering and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2011.