Rathore, Damandeep Singh;
(2022)
Novel Tools to Investigate Cortical Activity in Paroxysmal Disorders.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
This PhD project is at the interface between academic research and industry, and is jointly sponsored by the BBSRC and the industrial partner– Scientifica UK. The goal of this research is the development of new instruments and approaches to monitor and manipulate neuronal network activity in disease states. Firstly, (I) I collaborated with Scientifica to develop and utilise the newly developed Laser Applied Stimulation and Uncaging (LASU) system. The combined usage of the LASU system, alongside novel spatially-targeted channelrhodopsin variants, has al- lowed me to test the limits of single-photon optogenetic stimulation in achieving specific activation of targeted neurons. The presented findings demonstrate that, al- though high-resolution stimulation is achievable in the rodent cortex, single-photon stimulation is insufficient to achieve single-cell resolution stimulation. Secondly, (II) I have combined the high temporal resolution of novel, transparent 16-channel epicortical graphene solution-gated field effect transistor (gSGFET) arrays with the large spatial coverage of bilateral widefield Ca2+ fluorescence imaging; to per- form investigations of the relationship between spreading depolarisation (SD) and cortical seizures in awake head-fixed mouse models of epilepsy. To analyse these complex datasets, I developed a bespoke, semi-automated analysis pipeline to pro- cess the data and probe the seizure-SD relationship. I present the advantages of this dual-modality approach by demonstrating the strengths and weaknesses of each recording method, and how a synergistic approach overcomes the limitations of each technique alone. I utilise widefield imaging to perform systematic classification of SD and seizures both temporally and spatially. Detailed electrophysiological anal- ysis of gSGFET data is then performed on extracted time periods of interest. This work demonstrates the complex interaction between seizures and SD, and proposes several mechanisms describing these interactions. The technological and analytical tools presented here lay the groundwork for insightful and flexible experimental paradigms; altogether, able to probe paroxysmal activity in profound detail.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Novel Tools to Investigate Cortical Activity in Paroxysmal Disorders |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10157571 |
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