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Mechanisms of Deep Brain Stimulation Revealed by Optogenetic Deconstruction of Diseased Brain Circuitry

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Mechanisms of Deep Brain Stimulation Revealed by Optogenetic Deconstruction of Diseased Brain Circuitry MECHANISMS OF DEEP BRAIN STIMULATION REVEALED BY OPTOGENETIC DECONSTRUCTION OF DISEASED BRAIN CIRCUITRY A DISSERTATION SUBMITTED TO THE DEPARTMENT OF NEUROSCIENCES AND THE COMMITTEE ON GRADUATE STUDIES OF STANFORD UNIVERSITY IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY Viviana Gradinaru June 2010 © 2010 by Viviana Gradinaru. All Rights Reserved. Re-distributed by Stanford University under license with the author. This work is licensed under a Creative Commons Attribution- Noncommercial 3.0 United States License. http://creativecommons.org/licenses/by-nc/3.0/us/ This dissertation is online at: http://purl.stanford.edu/rj878dv3879 ii I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Karl Deisseroth, Primary Adviser I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Helen Bronte-Stewart I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Paul Buckmaster I certify that I have read this dissertation and that, in my opinion, it is fully adequate in scope and quality as a dissertation for the degree of Doctor of Philosophy. Carla Shatz Approved for the Stanford University Committee on Graduate Studies. Patricia J. Gumport, Vice Provost Graduate Education This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file in University Archives. iii iv Abstract Deep brain stimulation (DBS) is a powerful therapeutic option for intractable movement and affective disorders (Parkinson’s disease or PD, tremor, dystonia, Tourette syndrome, chronic pain, obsessive compulsive disorder, depression, bipolar). The benefits of DBS are immediate and dramatic, manifested as instantaneous improvements in motor function in the case of PD patients. However, due to the nonspecificity of electrical stimulation, DBS has variable efficacy and can lead to serious side effects. The mechanisms behind the effects of DBS are still highly controversial and there is tremendous interest from both neuroscience and clinical communities to understand and improve DBS. We have developed a novel technology based on two microbial opsins, Channelrhodopsin (ChR2) and Halorhodopsin (NpHR), that allows to directly and specifically control the activity of distinct cell-types with high temporal precision in well defined brain regions, therefore allowing us to overcome the lack of specificity of electrical DBS. This study provides the first investigation of the role of specific cell types in ameliorating PD symptoms addressed by effective DBS treatment. The focus of the thesis was twofold: (1) to develop and optimize optogenetic technologies (molecular and hardware) for safe and effective use in behaving mammals; and (2) to employ the above developed optogenetic toolkit to deconstructing diseased brain circuitry, with focus on Parkinson’s disease. The framework and technological toolbox presented here can be employed across many brain circuits to selectively control individual components and therefore systematically deconstruct intact and disordered brain processes. v vi Preface The work presented in this thesis consists of five published studies, as described below. These studies, listed in chronological order except the introductory chapter 1, focused on early optogenetic development (Chapters 1 and 2), using optogenetics to understand diseased brain circuitry (Chapter 3), providing the scientific community with a detailed list of protocols for optogenetic applications (Chapter 4) and advancing the optogenetic tools to new levels of potency and generalizing cellular targeting means for optogenetics (Chapter 5). CHAPTER 1 – Introduction, based on a published manuscript by Schneider, M.B., Gradinaru, V., Zhang, F., and Deisseroth, K. (2008). Controlling neuronal activity. The American journal of psychiatry 165, 562. This is a very brief introduction to optogenetics and how it relates to application to neurological disorders. The article was written by Bret and Karl; Feng and I contributed the figure panels and text comments. CHAPTER 2 – Gradinaru, V., Thompson, K.R., Zhang, F., Mogri, M., Kay, K., Schneider, M.B., and Deisseroth, K. (2007). Targeting and readout strategies for fast optical neural control in vitro and in vivo. J Neurosci 27, 14231-14238. This was an article reviewing the early versions of ChR2 and NpHR and introducing: (1) an enhanced ChR2 version for neuronal applications; (2) intracellular and intercellular targeting means for optogenetics; (3) a simultaneous recording-stimulation device, the optrode; (4) the first in vivo demonstration of motor control using optogenetics. This article was written by me and Karl. All the experiments were carried out by me in collaboration with the other authors on the paper. CHAPTER 3 – Gradinaru, V.*, Thompson, K.R.*, and Deisseroth, K. (2008). eNpHR: a Natronomonas halorhodopsin enhanced for optogenetic applications. Brain cell biology 36, 129-139. *Equal contribution. This study came as a neccesity to develop an NpHR variant that would be well tolerated at high expression levels and functional in the intact mammalian brain. I generated the molecular variants of NpHR and vii performed in vitro and in vivo electrophysiology and Kim performed the toxicity assays and immunocytochemistry; we wrote the paper together with Karl. CHAPTER 4 – Gradinaru, V.*, Mogri, M.*, Thompson, K.R., Henderson, J.M., and Deisseroth, K. (2009). Optical deconstruction of parkinsonian neural circuitry. Science (New York, NY 324, 354-359. *Equal contribution. This study, which was my main Ph.D. thesis and qualifying proposal, was conceived through collaboration with Karl Deisseroth and Jaimie Henderson. We looked at the mechanisms behind Deep Brain Stimulation in animal models of Parkinson’s disease using optogenetics tools in the development of which I was involved in the first 2 years of my PhD. Most of the experiments were conducted by me and Murtaza, with help from Kim Thompson with immunohistochemistry. The main text was written primarily by me and Karl, with help from Murtaza, who wrote the supplementary information with help from me. CHAPTER 5 – Zhang, F.*, Gradinaru, V.*, Adamantidis, A.R.*, Durand, R., Airan, R.D., de Lecea, L., and Deisseroth, K (2010). Optogenetic interrogation of neural circuits: technology for probing mammalian brain structures. Nature protocols 5, 439- 456. *Equal contribution. This study came as a neccesity to have a comprehensive collection of optogenetics techniques that the scientific community could access for their own studies. The paper describes the numerous constructs, hardware, and techniques, developed over more than 5 years by all members of the Deisseroth lab and by Antoine Adamantidis in the de Lecea lab. Feng, me, and Antoine contributed equally to the writing and figures in the paper. The sections on VSDI were the exclusive contribution of Remy Durand and Raag Airan; because I did not personally performed VSDI during graduate school, I removed the selected sections from this thesis. CHAPTER 6 – Gradinaru, V.*, Zhang, F.*, Ramakrishnan, C., Mattis, J., Prakash, R., Diester, I., Goshen, I., Thompson, K.R., Deisseroth, K. Molecular and Cellular Approaches for Diversifying and Extending Optogenetics. Cell. 2010 Apr. *Equal contribution. This study was conceived through collaboration with Karl and Feng. Karl and I wrote the paper with help from Feng and Joanna. I carried out most of the experiments in collaboration with the co-authors on the paper. The paper introduces viii the latest generation of optogenetic tools, which includes highly potent inhibitors that span the visible spectrum, including the infrared border, and promoter-free targeting methods for optogenetics. ix x Acknowledgements Stanford has been a wonderful environment for my scientific and personal growth. The Neuroscience program has been truly a home away from home for me, a student from Romania. Being part of the new exciting center, the Bio-X, and supported by wonderful fellowships such as the SGF and SIGF, I had little limits to what I could attempt and achieve. The Deisseroth lab was a playground full of possibilities and working there day by day and witnessing the development of a new area in Neuroscience has been tremendously rewarding and motivating. I am deeply grateful to my advisor Karl Deisseroth for his scientific and personal guidance. He has been a model for hard work, passion, and excellence. His energy seemed endless and intimidating at times but he nevertheless carries himself with such modesty and candor. I saw the lab growing from a handful of people, mainly graduate students, assembling incubators and rigs, and trying to figure out their way, to a fully mature lab with many highly skilled and intelligent people and amazing resources. I am grateful to Karl for the environment that he provided all of us with so that we can do science and I hope I can follow in his steps and become a collaborative, contributing, member to the scientific community. The help and support of the entire Deisseroth lab and many members of the Stanford community was crucial to me completing all these projects in the last four years. In particular I would
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