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Investigating C. Elegans Escape Responses with Biophotonics and Machine Vision Investigating C. elegans Escape Responses with Biophotonics and Machine Vision BY JᴀRᴌᴀᴛH D. BYRNᴇ RᴏᴅGᴇRS A ᴛHᴇSIS SᴜBᴍIᴛᴛᴇᴅ IN ᴄᴏNFᴏRᴍIᴛY ᴡIᴛH ᴛHᴇ RᴇQᴜIRᴇᴍᴇNᴛS FᴏR ᴛHᴇ ᴅᴇGRᴇᴇ ᴏF DᴏᴄᴛᴏR ᴏF PHIᴌᴏSᴏᴘHY Cᴇᴌᴌ ᴀNᴅ SYSᴛᴇᴍS BIᴏᴌᴏGY UNIᴠᴇRSIᴛY ᴏF TᴏRᴏNᴛᴏ © CᴏᴘYRIGHᴛ BY JᴀRᴌᴀᴛH D. BYRNᴇ RᴏᴅGᴇRS 2020 Investigating C. elegans Escape Responses with Biophotonics and Machine Vision JᴀRᴌᴀᴛH D. BYRNᴇ RᴏᴅGᴇRS DᴏᴄᴛᴏR ᴏF PHIᴌᴏSᴏᴘHY Cᴇᴌᴌ ᴀNᴅ SYSᴛᴇᴍS BIᴏᴌᴏGY UNIᴠᴇRSIᴛY ᴏF TᴏRᴏNᴛᴏ 2020 Abstract One of the fundamental goals in neuroscience is to describe how animals process information from their environment, integrate it with past experience and internal physiological states, and output an appropriate behavioral response. This goal has remained elusive, however, even in circuits as small as the adult nervous system of the nematode Caenorhabditis elegans, with just 302 neurons, and even in frequently studied and apparently simple behaviors, such as the escape response. This thesis presents work towards achieving this goal by developing tools to quantify the behavioral complexity of the C. elegans escape from rapidly increasing temperature. We developed a system that tracks the behavior of individual freely behaving worms, and simultaneously targets infrared laser stimuli to small body regions. We showed that certain aspects of the escape response last for several minutes, and vary with experience, environment and immediate behavioral state. Equipped with these tools for applying precise stimuli and quantitatively measuring behavior, we characterized the worm’s response to repeated stimulation. Escape responses habituate over time, and high-content phenotyping revealed that different behavioral metrics reflect different rates of learning, which suggests multiple loci of plasticity for this simple form of learning. The stimulation and tracking system has also proven useful for other projects: first, it helped test hypotheses derived from whole-brain calcium imaging, in particular confirming that the AWCOFF neuron has a role in the ii noxious heat response. Second, a behavioral dataset of heat-induced escape responses helped collaborators describe the worm’s shape through self-occluding turns, an important behavior. We also describe methods for applying similar thermal stimuli while recording neuronal activity with genetically encoded calcium indicators and for measuring temperature with high precision. These techniques were used to identify a novel role for the PVD neurons as midbody thermosensors in C. elegans. Taken together, this thesis demonstrates the utility of combining precise control of environmental stimuli with high-dimensional phenotyping for understanding how a small nervous system controls sensory behavior. iii Acknowledgments I am grateful for the support of the many individuals who made the completion of this thesis possible. Thank you first to my supervisor Professor Will Ryu. I have learned a great deal from Will since we met in my freshman year Integrated Science course thirteen years ago. Will brought together a wonderful group of people in the Ryu Lab, several of whom I was fortunate to work with, and to call not only colleagues but friends. Thank you to my supervisory committee members Joel Levine and Mei Zhen, each of whom brought their unique perspectives to my committee meetings over the years. This thesis is stronger because of them. Thank you to Chris V. Gabel and Tod Thiele for enthusiastically joining my examination committee. Thank you to my collaborators from the Ryu, Stephens and Kalia Labs, especially Aylia Mohammadi, Ippei Kotera, Onno Broekmans, Greg Stephens and Krystal Menezes. I enjoyed working with Byron Wilson on the original track and zap system when he was an undergraduate. I was supported in this work by the Natural Sciences and Engineering Research Council of Canada (NSERC) through a Postgraduate Scholarship (PGS-M) and an Alexander Graham Bell Canada Graduate Scholarship (CGS-D). This dissertation was typeset in Michael Sharpe’s fbb with LATEX, using a version of Jordan Suchow’s Dissertate template. As I reflect on my path to the end of this doctoral thesis, I am reminded of its beginning. I feel very fortunate to have met David Botstein and learned from him about the new Integrated Science curriculum at Princeton before choosing my first year undergraduate courses. In Integrated Science I learned from many inspiring iv teachers and scientists, in particular Professors William Bialek, Leonid Kruglyak, Clarence Schutt and Eric Wieschaus, and made many close friends. Thank you to Amy Caudy, Gunnar Kleemann and my undergraduate thesis advisor Coleen Murphy for first exposing me to worms, and for providing the supportive foundation that made possible my first independent research projects. Finally, thank you to my friends and family, whose support has been unwavering and incredibly helpful and important. I am especially grateful to my parents Miriam Byrne and Kim Rodgers. v Contents 1 INᴛRᴏᴅᴜᴄᴛIᴏN Ο 1.0.1 Quantifying behavior ................................................. 2 1.0.2 C. elegans escape........................................................ 2 1.0.3 Thermosensory behaviors in C. elegans .............................. 3 1.0.4 Outline ................................................................. 4 2 TᴀRGᴇᴛᴇᴅ ᴛHᴇRᴍᴀᴌ SᴛIᴍᴜᴌᴀᴛIᴏN ᴀNᴅ HIGH-ᴄᴏNᴛᴇNᴛ ᴘHᴇNᴏᴛYᴘING Rᴇᴠᴇᴀᴌ ᴛHᴀᴛ ᴛHᴇ C. ᴇᴌᴇGᴀNS ᴇSᴄᴀᴘᴇ RᴇSᴘᴏNSᴇ INᴛᴇGRᴀᴛᴇS ᴄᴜRRᴇNᴛ BᴇHᴀᴠIᴏRᴀᴌ Sᴛᴀᴛᴇ ᴀNᴅ ᴘᴀSᴛ ᴇXᴘᴇRIᴇNᴄᴇ. Τ 2.1 Introduction .................................................................... 6 2.2 Results ........................................................................... 7 2.2.1 System for long term tracking and targeted thermal stimulation of individual C. elegans combined with high-content behavioral phenotyping .............................. 7 2.2.2 Noxious thermal stimuli at the head elicit robust escape responses and induce an arousal state that lasts for several minutes 9 2.2.3 Stimulus strength affects both the probability and magnitude of the escape response ................................................. 13 2.2.4 Food context changes escape and unstimulated behaviors......... 15 2.2.5 Escape strategy depends on initial behavioral state ................. 17 2.2.6 Escape reversals must be completed before additional stimuli can evoke a response .................................................. 19 2.2.7 Response to thermal stimuli habituates after multiple encounters 22 2.2.8 Long-term thermal experience modulates escape response........ 23 2.3 Discussion ....................................................................... 26 2.4 Materials and methods ......................................................... 29 2.4.1 Strain cultivation ...................................................... 29 2.4.2 Applying repeated thermal stimuli to freely behaving animals.... 29 2.4.3 Data analysis ........................................................... 32 2.5 Acknowledgments ............................................................. 36 vi 3 BᴇHᴀᴠIᴏRᴀᴌᴌY ᴅISᴛINᴄᴛ HᴀBIᴛᴜᴀᴛIᴏN RᴀᴛᴇS IN ᴛHᴇ C. ᴇᴌᴇGᴀNS RᴇSᴘᴏNSᴇ ᴛᴏ NᴏXIᴏᴜS Hᴇᴀᴛ. ΡΥ 3.1 Introduction .................................................................... 37 3.2 Results ........................................................................... 39 3.2.1 The C. elegans response to noxious heat habituates after repeated encounters with a short, rapidly increasing stimulus .... 39 3.2.2 Multiple components of the escape behavior habituate at different rates .......................................................... 39 3.2.3 Habituation dynamics of distinct response components are separable by stimulus intensity and genotype ...................... 41 3.3 Discussion ....................................................................... 46 3.4 Materials and methods ......................................................... 47 3.4.1 Strain cultivation ...................................................... 47 3.4.2 Thermal stimulation assay ............................................ 47 3.4.3 Behavioral metrics ..................................................... 47 4 TᴇᴄHNIᴄᴀᴌ ᴄᴏNSIᴅᴇRᴀᴛIᴏNS ᴀNᴅ ᴄᴏᴌᴌᴀBᴏRᴀᴛIᴠᴇ ᴀᴘᴘᴌIᴄᴀᴛIᴏNS ΢Χ 4.1 Simultaneous application of thermal stimuli and multi-channel fluorescent imaging for measuring neuronal activity and temperature ... 51 4.1.1 Introduction............................................................ 51 4.1.2 Results .................................................................. 52 4.1.3 Materials and methods ................................................ 58 4.2 Image registration-based determination of microscope stage movement for single worm tracking ......................................... 60 4.2.1 Approach and results .................................................. 60 4.3 Collaborative applications ..................................................... 66 4.3.1 Measuring neuronal calcium signals to identify PVD as a noxious heat sensing neuron at the midbody ....................... 66 4.3.2 Pan-neuronal screening in C. elegans reveals asymmetric dynamics of AWC neurons is critical for thermal avoidance behavior ................................................................ 69 4.3.3 Resolving coiled shapes reveals new reorientation behaviors in C. elegans................................................................ 70 5 CᴏNᴄᴌᴜSIᴏN ΥΠ RᴇFᴇRᴇNᴄᴇS ΥΣ vii List of figures 1.1 C. elegans sensory neurons that respond to noxious temperature .......... 4 2.1 High spatiotemporal resolution thermal stimulation of freely behaving C. elegans
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