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From the Left to the Right a Tale of Asymmetries, Environments, and Hippocampal Development

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From the Left to the Right a Tale of Asymmetries, Environments, and Hippocampal Development From the left to the right A tale of asymmetries, environments, and hippocampal development by Matthew Case June, 2018 A thesis presented to the Graduate School of the Institute of Science and Technology Austria, Klosterneuburg, Austria in partial fulfilment of the requirements for the degree of Doctor of Philosophy The dissertation of Matthew Case, titled ‘From the left to the right: A tale of asymmetries, environments, and hippocampal development’, is approved by: Supervisor: [Name of Supervisor], IST Austria, Klosterneuburg, Austria Signature: Committee Member: [Name of Committee Member], IST Austria, Klosterneuburg, Austria Signature: Committee Member: [Name of Committee Member], [Institute], [City], [Country] Signature: Exam Chair: [Name of Exam Chair], IST Austria, Klosterneuburg, Austria Signature: © by Matthew Case, June, 2018 All Rights Reserved I hereby declare that this dissertation is my own work and that it does not contain other people’s work without this being so stated; this thesis does not contain my previous work without this being stated, and the bibliography contains all the literature that I used in writing the dissertation. I declare that this is a true copy of my thesis, including any final revisions, as approved by my thesis committee, and that this thesis has not been submitted for a higher degree to any other university or institution. I certify that any republication of materials presented in this thesis has been approved by the relevant publishers and co-authors. Signature: _______________________ [Matthew J Case] June 27, 2018 “Symmetry is what we see at a glance; based on the fact that there is no reason for any difference...” ― Blaise Pascal, Pensées Dedication I'd like to offer a joint dedication for this thesis. Firstly, to all the mice I used in these experiments. Mice and rats often suffer in our relentless (though arguably necessary) pursuit of knowledge and although they might not appreciate (or even understand) the nod of thanks; I feel that, as scientists, it's important for us not to forget the fact that laboratory animals are not thoughtless robots, which exist only for our benefit. Secondly, having given a sincere offering of gratitude to the powerless, I'd like to also present an insincere one to the powerful. The second part of my dedication is given to Cthulhu. Like us humble men of science, may you never stop dreaming. Abstract Asymmetries have long been known about in the central nervous system. From gross anatomical differences, such as the presence of the parapineal organ in only one hemisphere of the developing zebrafish, to more subtle differences in activity between both hemispheres, as seen in freely roaming animals or human participants under PET and fMRI imaging analysis. The presence of asymmetries has been demonstrated to have huge behavioural implications, with their disruption often leading to the generation of neurological disorders, memory problems, changes in personality, and in an organism's health and well-being. For my Ph.D. work I aimed to tackle two important avenues of research. The first being the process of input-side dependency in the hippocampus, with the goal of finding a key gene responsible for its development (Gene X). The second project was to do with experience- induced laterality formation in the hippocampus. Specifically, how laterality in the synapse density of the CA1 stratum radiatum (s.r.) could be induced purely through environmental enrichment. Through unilateral tracer injections into the CA3, I was able to selectively measure the properties of synapses within the CA1 and investigate how they differed based upon which hemisphere the presynaptic neurone originated. Having found the existence of a previously unreported reversed (left-isomerism) i.v. mutant, through morpholocal examination of labelled terminals in the CA1 s.r., I aimed to elucidate a key gene responsible for the process of left or right determination of inputs to the CA1 s.r.. This work relates to the previous finding of input-side dependent asymmetry in the wild-type rodent, where the origin of the projecting neurone to the CA1 will determine the morphology of a synapse, to a greater degree than the hemisphere in which the projection terminates. Using left- and right- isomerism i.v. mice, in combination with whole genome sequence analysis, I highlight Ena/VASP-like (Evl) as a potential target for Gene X. In relation to this topic, I also highlight my work in the recently published paper of how knockout of PirB can lead to a lack of input- side dependency in the murine hippocampus. For the second question, I show that the environmental enrichment paradigm will lead to an asymmetry in the synapse densities in the hippocampus of mice. I also highlight that the nature of the enrichment is of less consequence than the process of enrichment itself. I 8 demonstrate that the CA3 region will dramatically alter its projection targets, in relation to environmental stimulation, with the asymmetry in synaptic density, caused by enrichment, relying heavily on commissural fibres. I also highlight the vital importance of input-side dependent asymmetry, as a necessary component of experience-dependent laterality formation in the CA1 s.r.. However, my results suggest that it isn't the only cause, as there appears to be a CA1 dependent mechanism also at play. Upon further investigation, I highlight the significant, and highly important, finding that the changes seen in the CA1 s.r. were predominantly caused through projections from the left-CA3, with the right-CA3 having less involvement in this mechanism. 9 Acknowledgements I'd like to offer particular thanks to the following: Professor Ryuichi Shigemoto, my supervisor, for providing me with invaluable guidance and support throughout my PhD studies. Professor Isao Ito, for providing me with different genetic mice lacking input-side dependent asymmetries, such as the original i.v. and the PirB ko mouse mutants. Professor Shuji Shigenobu, for generation of the Illumina sequence libraries and help with whole genome sequence analysis to try and determine Gene X. David Kleindienst, for design of the AAV virus used in my enriched environment experiments, as well as helping write a script to narrow down SNPs to only those appearing within genes on chromosome 12. As well as to the rest of the Shigemoto lab, both those from the National Institute of Physiological Sciences (Okazaki, Japan), and those from the Institute of Science and Technology (Austria), for being a great bunch of people to spend a PhD with and supporting as only members of the same lab can. 10 About the Author Matthew Case completed a BSc in Biological Sciences at the University of Plymouth and an MSc in Stem Cells and Regenerative Medicine at the University of Bristol, before joining the IST Austria in April. His main research interests focus on the impact of input-side dependent asymmetry formation in the hippocampus, both in its formation and in its effect on hippocampal synapse modulation during experience-dependent learning. During his PhD studies, Matthew has published his results on the regulatory effect of PirB (discussed within this thesis) was in the journal PLoS ONE (Ukai H 2017) and has discussed his work on the effect of environmental enrichment in modulating experience-dependent hippocampal laterality formation in the Japanese Neuroscience Society Symposium (JNSS) in 2017. 11 List of Publications Appearing in Thesis 1. Ukai, H. et al. PirB regulates asymmetries in hippocampal circuitry. PLoS One 12, 1– 20 (2017). 12 Table of Contents List of figures ...............................................................16 List of common abbreviations ...............................................................19 Chapter 1 The developmental underpinnings of input-side dependent asymmetry in the murine hippocampus Chapter introduction ...............................................................20 1:1 Determining isomerism by morphology alone Introduction ...............................................................34 Methods, results, and brief discussion ...............................................................35 1:2 Finding a right-isomerism i.v. mouse line close to the spontaneous right to left-isomerism switch Introduction ...............................................................39 Methods, results, and brief discussion ...............................................................40 1:3 Comparing left- and right-isomerism i.v. mice Introduction ...............................................................43 Methods, results, and brief discussion ...............................................................44 1:4 Crossing left- and right-isomerism i.v. mice Introduction ...............................................................48 Methods, results, and brief discussion ...............................................................49 1:5 Back-crossing pups from the F1 generation with their father to investigate whether a single gene is responsible for left-right determination Introduction ...............................................................51 Methods, results, and brief discussion ...............................................................52 1:6 Whole genome sequence analysis of parents and offspring to try and isolate Gene X Introduction ...............................................................56 Methods, results, and brief discussion ...............................................................57 1:7 Confirming
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