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The Development of a High Speed 3D 2-Photon Microscope for Neuroscience

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The Development of a High Speed 3D 2-Photon Microscope for Neuroscience The Development of a High Speed 3D 2-photon Microscope for Neuroscience Paul Anthony Kirkby UCL Doctor of Philosophy 1 Declaration I, Paul Anthony Kirkby, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Abstract The progress of neuroscience is limited by the instrumentation available to it for studying the brain. At present, there is a serious instrumentation gap between functional Magnetic Resonance Imaging (fMRI) of whole brains and the microscopic scale functional imaging possible with today’s optical microscopes and electrophysiology techniques, such as patch clamping of individual neurons. This thesis describes the development of a new extension to optical microscopy that enables refocusing within 25 microseconds rather than the large fraction of a second possible by moving the sample or objective. The system is capable of refocusing a laser beam that is monitoring activity in 3D samples of live brain tissue 300 times faster than previously possible. This will make practical a new type of optical functional imaging for studying small sub-networks of neurons containing up to about 30,000 neurons at up to 30,000 sub micrometre sized monitored points of interest per second. The thesis describes the development of a detailed design for a new type of 3D scanner that uses Acousto-Optic Deflectors (AODs) to diffractively deflect and focus an intense laser beam beneath a conventional microscope objective. The fluorescence of calcium sensitive dyes in live neurons is used to monitor action potentials conveying signals between neurons. The optical and systems engineering problems and design trade-offs involved are discussed in detail. The results of extensive computer modelling are described and innovative solutions to several key optical physics based engineering problems are explained. The practical problems found in building a prototype machine incorporating these innovations are described and the encouraging first operational results from the machine reported. 2 Acknowledgements I am very grateful for the opportunity that this PhD and preceeding MRes has given me to retrain from optoelectonics research engineering into neuroscience instrumentation. I am indebted to the EPSRC/BBSRC funded UCL Centre for Mathematics Physics Life Sciences and Experimental biology (CoMPLEX, http://www.ucl.ac.uk/complex/ ) and in particular to Andrew Pomianowski, Guy Moss and Alan Johnstone three of its directors for agreeing to take a chance on such a ‘mature’ student at the beginning and for supporting and encouraging me throughout. This project was conceived by Angus Silver in 2004 and a pilot project was funded by EPSRC starting in 2005 (Silver 2004). It has been a great pleasure to be part of the Silver Lab that Angus leads so effectively. This project has been carried out predominantly by K M N Srinivas Nadella, a Research Fellow and myself, with very regular discussion and leadership from Angus. During the 4 years of the thesis I have also had funding support from The Worshipful Company of Scientific Instrument Makers since I won their ‘Beloe Fellowship’ in 2008. Angus Silver has also used part of his Welcome Trust, Medical Research Council Fellowships to support the overall project and extend my student grant. There are many different skills and attributes required to progress the development of such a complex instrument as described in this Thesis. At each stage, I have done the initial conceptual work and Matlab modeling for all the aspects of the work described in the thesis (except the temporal compensator). I have developed the concepts and implemented all the Matlab code described here for controlling the AOL laser spot position vs. time. Srinivas has done the majority of the experimental implementation, such as optical train assembly and alignment and the development and implementation of all the LabView code that provides the user interface. The results presented in Chapter 5 include our first demonstrations of the feasibility of the microscope for 3D biological functional imaging at kHz rates. This work was carried out by Tomas Fernandez-Alfonso and Srinivas. Srinivas also designed and carried out the experimental measurements of temporal dispersion compensation. All the other experimental work described in this thesis was carried out jointly by myself 3 and Srinivas. We are very grateful to Alan Hogben and Duncan Farqueharson for the high quality mechanical work that has been carried out by the UCL Biosciences Engineering workshop and to Bruno Pichler for much help with software development. I would like to thank Warren Seale and Mike Draper of Gouch and Housego (www.goochandhousego.com ) for their advice and help with AOD design and analysis of performance and Mike Hillier of Isomet (www.isomet.com ) for his enthusiastic development of improved versions of the iDDS for this project. Particularly at the beginning of the project, Bill Vogt and Todd Keifer of Prairie Technologies (www.prairie-technologies.com) were very helpful in training us in microscope engineering and throughout the project Mike Szulczewski CEO of Prairie has provided enthusiastic support and strategic advice in a business context. Abigail Watts of UCL Business has been our guardian in UCL business and overseen the project from the perspective of its commercial exploitation. Mark Roberts of JA Kemp Patent Attourneys has been a pleasure to work with and suggested the clarification I used on the way the ramp rate equations in chapter 3 were presented. Finally I would like to thank John Mitchell of UCL Electrical Engineering, and my other colleagues in the Silver Lab and the wider UCL community for many inspiring useful and enjoyable conversations. At home I would like to thank my wife Geraldine for her support and encouragement throughout the course of this PhD and Geraldine, Valerie Shephard and my sister Margaret Kirkby for enthusiastic style advice and proof reading. I take responsibility for the remaining errors. Glossary AFL Absolute Frequency Limit; the first miniscan drive algorithm described graphically in Figure 2.24 for setting miniscan start and stop drive frequencies based on predefined absolute frequency limits. AOD acousto-optic deflector AOL acousto-optic lens 4 AOLM acousto-optic lens microscope DOE diffractive optical element FOV field of view FWHM full width half maximum neuronal processes the dendrites or axons of a neuron HWP half wave plate PMT photomultiplier tube psf point spread function: the 3D distribution of optical energy (or 2-photon excitation) at the focus of a lens OFL Optimised Frequency Limit: an algorithm of optimising the pairs of drive frequencies for the AODs on each axis to maximise efficiency and minimise efficiency variation during a miniscan RF radio frequency ROI region of interest telecentric relay an optical system, usually a pair of lenses that relay an input image to an output field .It has the property of constant magnification independent of z position. voxel the 3D equivalent of a 2D pixel , a ‘volume pixel’ 5 Table of Contents Declaration....................................................................................................................2 Abstract.........................................................................................................................2 Acknowledgements ......................................................................................................3 Glossary ........................................................................................................................4 Table of Contents .........................................................................................................6 Chapter 1 Introduction and background ..................................................................9 Biological objective – Understanding how the brain process information in its neural networks........................................................................................................10 Signal Processing in the neural networks of the brain.........................................12 2-photon Microscopy – principles, and limits to speed and duty cycle...................19 Basic principles....................................................................................................19 Fluorescent dyes for functional optical imaging..................................................22 2D vs. 3D – number of addressable neurons that can be chosen for optical functional imaging ...............................................................................................24 Options for high speed 3D focusing ....................................................................25 Introduction to AODs for scanning, pointing and focusing.....................................27 Principle of operation of AODs ...........................................................................27 Forming a spherical lens with AODs...................................................................29 Proposed overall system layout ...........................................................................35 Summary of objectives and challenges....................................................................37 Target specification..............................................................................................37 Summary of the state of the art for 3D AOD deflectors at the start of the PhD and primary challenges...............................................................................................37
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