Development of ultrasonic probes to modulate synaptic activity of human stem cell-derived cortical neurons (GW4 BioMed MRC DTP PhD Studentship)

Overview:

Non-invasive neuronal stimulation is an emerging approach to modulate cell function, with various clinical applications. We will develop novel ultrasonic techniques to evoke electrochemical signalling in human stem cell-derived neurons. This will inform ultrasonic use in basic research and outline a framework for novel non-invasive therapeutics.

Project details:

Changing the activity of neural circuits in the brain underpins many therapies that treat neurological diseases. Diverse methods are used to control neuronal function, from pharmacological compounds (e.g. agonists/antagonists) to direct electrical stimulation (e.g. deep-brain stimulation). However, techniques to modulate neuronal function noninvasively - with high spatial and temporal control - remain limited. One emerging approach is the use of low-intensity ultrasound to control the activity of neurons. This cutting-edge technique is very much in its infancy. The mechanisms responsible for ultrasound-regulated neuronal activity remain incompletely understood.

This project therefore seeks to develop and utilise ultrasonic probes to modulate the activity of human pluripotent stem cell (hPSC)-derived cortical neurons in vitro. Using this highly novel approach, we will determine the cellular mechanisms by which ultrasound can be used to control neuronal function. The project is composed of three components, where:

1. The student will examine the effects of ultrasound stimulation on synaptic transmission of hPSC-derived cortical neurons. We will characterise the mechanisms by which ultrasonic stimuli modulate neuronal function. We will focus on the effects on glutamatergic synaptic transmission using cutting-edge electrophysiology and ion imaging.

2. The student will derive and maintain hPSC cultures. Here we will optimise existing culture preparation and infrastructure to meet the requirements of the ultrasonic stimulation paradigm.

3. The student will use modelling and simulation to characterise appropriate ultrasonic beam profiles, from which they will develop probes and interfacing rigs for use with the neuronal cultures.

The project will be conducted across the University of Bristol (Bristol Medical School) and Cardiff University (Neurosciences & Mental Health Research Institute) where the synaptic function assays (e.g., whole-cell patch clamp electrophysiology; calcium imaging using fluorescence microscopy) and basic cell culture (e.g., differentiation of hPSCs) will be performed. The design and field simulation of the ultrasonic probes will be undertaken in the Ultrasonics Group (Department of Mechanical Engineering, University of Bristol). The development and implementation of the probes will be performed at our industrial partner The

Welding Institute (TWI), a global leader in the development and use of ultrasonic devices (Newport, Wales).

Project outcomes:

The anticipated outcomes from the project include revealing the mechanisms underlying ultrasonic-mediated regulation of neuronal activity and, crucially, the development of a novel ultrasonic probe, designed to stimulate neurons with high spatial specificity. This could well open new avenues of implementation of such devices in novel therapeutic approaches.

Supervisory Team:

Dr Daniel Whitcomb, Bristol Medical School, University of Bristol

Professor Bruce Drinkwater, Department of Mechanical Engineering, University of Bristol

Dr Eunju Jenny Shin, College of Biomedical and Life Sciences, Cardiff University

Dr Miles Weston, The Welding Institute (TWI), Newport, Wales

The deadline for applications is 5:00pm on 23rd November 2018.

The DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics, statistics and the physical or social sciences.