Kӧse-Dunn, Matthew James (2019) Engineering and optimising a functional in vitro model of basal ganglia circuitry. Doctoral thesis, Keele University.

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Abstract

The majority of neurological diseases (such as Parkinson’s and Huntington’s diseases) are progressive, debilitating and currently incurable. In an ageing population, the prevalence of such diseases will only increase over time, creating a need for better pre-clinical tools that allow for more research into such diseases, as clinical trails are expensive and time-consuming. In this thesis I describe the development and optimisation of a pre-clinical in vitro neural model of functional basal ganglia circuitry. When this circuitry in the basal ganglia breaks down or is damaged, it can result in Parkinson’s or Huntington’s diseases, and by modelling these areas in both a healthy and damaged state in vitro we create a powerful platform for pre-clinical research into neurological disease. The model described here is a microfluidic compartmentalised device consisting of five sections linked by micro-scale channels, designed in AutoCAD and fabricatd by soft lithography. The design of this model allows for neural cell populations to be simultaneously isolated and connected, as axons grow through the channels to adjacent sections and create a neural circuit. The design of the device, chemical coating and microchannel width were all optimised in order for the device to better mimic the basal ganglia, culturing primary cells obtained from the cortex, striatum, globus pallidus and substantia nigra of rat embryos within the device. Extracellular recording methods were also introduced, using a multi-electrode array (MEA) in order to record spontaneous electrophysiological activity from the neural cultures (whether seperate or connected) and determine that the cells were functional. The effects of connectivity on functionality was determined across all relevant co-cultures. In order to make the device a mimic of Parkinson’s disease, 6-OHDA was used to damage/destroy nigrostriatal dopamine neurons, and the effects of this loss on functionality were also assessed. The device is a powerful pre-clinical platform for research, modelling aspects of a healthy physiological basal ganglia and aspects of a damaged pathological Parkinsonian basal ganglia. The novel findings presented in this thesis show the potential of this microfluidic model to study basal ganglia circuitry and accelerate Parksinon’s research.

Item Type: Thesis (Doctoral)
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
Depositing User: Lisa Bailey
Date Deposited: 13 Jun 2019 13:16
Last Modified: 13 Jun 2019 13:16
URI: http://eprints.keele.ac.uk/id/eprint/6484

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