Joint Ph.D. Program

Thesis Topic : Microrobotic Electrode Placement for Neural Interfaces and Deep Brain Stimulation.

Research Theme: Develop novel tools to observe and stimulate neural activity.

Description: The project is part of a broader effort to develop micro/nanotechnology-based sensors and actuators to monitor and stimulate neural circuits in vitro and in vivo. The goal of the devices is to enable a better understanding of neurons and neural circuits, which will aid in the development of neuromedicine. The ability to map the activity of individual neurons will allow for high resolution recording of neural activity at a level not seen before. To this end, advanced probes are being developed to be implanted into brain tissue. However, the ability to place arrays of electrodes with single-neuron precision has not been achieved. In this project, the student will develop new electrode placement mechanisms based on smart material and/or magnetic actuation which allows for addressable precision placement of many electrode tips within an array. The student will work in the labs of Prof. Eric Diller at the University of Toronto and Metin Sitti at the Max Planck Institute for Intelligent Systems using multidisciplinary skills. With neurophysics collaborators, the student will develop prototypes for testing in phantom models to prove the efficacy for electrode placement and adjustment.

Thesis Topic : Towards restoration of E:I balance in Parkinson’s disease and dystonia.

Research Theme: analyze data, create models and make predictions about neural activity.

Description:

Many brain circuits operate in a dynamic state governed by the balance between excitation and inhibition (E:I balance). Fluctuations in E:I balance underlie various physiological functions, while aberrant shifts have been implicated in neurological and psychiatric disorders. Recent computational work has estimated E:I changes from the power law exponent of electrophysiological power spectra, as validated by extracellular neural data in rats and macaques. However, these methods have not yet been validated at the single-unit level, nor have consequences on circuit communication been studied in humans. We propose to leverage this exciting methodology to study the implications of E:I balance in movement disorders. In particular, opposing shifts in E:I balance have been postulated to give rise to the hypo- and hyperkinetic symptoms in Parkinson’s disease and dystonia, respectively. We propose to leverage intracranial recordings (single-neuron, local-field-potential, electrocorticography, magnetoencephalography) from the human basal-ganglia-thalamo-cortical network (BGTCN) to validate such hypotheses, and to explore the possibility for therapeutic restoration of E:I balance by manipulation of BGTCN circuitry using deep brain stimulation. Furthermore, we will seek a deeper understanding of these processes by mechanistic modelling of the BGTCN network using neural mass models, linking E:I balance to behavioral consequences, electrophysiological activity, and brain stimulation.

Thesis Topic : Spatially Resolved and Single-Cell Proteomics to Assess Physiological Microglia States.

Research Theme: To conduct neurobiology experiments that use advance tools.

Description:

We will develop a cutting-edge methodology - ex vivo digital microfluidic isolation of single cells for Omics (evDISCO) - to study transcriptomic and proteomic profiles of microglia in defined physiological states, focusing on functional consequences of neuronal inputs to microglia. Beyond their role in brain pathophysiology, microglia appear to also act as physiological regulators of brain function, by receiving specific input from surrounding neurons and feeding back regulatory information via chemical messengers and cell-cell contacts. We plan to explore the underlying biology by using evDISCO in microglia reporter mouse lines, focusing on the effects of neuronal signaling on microglia transcriptomes and proteomes in defined brain regions and single cells. To this end, our PhD student will comparatively profile microglia (i) from transmitter-secretion-deficient brains (organotypic Unc13 KO brain slices) to determine how overall circuit activity affects microglia states, and (ii) from multiple brain regions (e.g. frontal cortex, visual cortex, hippocampus, striatum, a.o.) to systematically assess how the specific neuronal environment defines specific microglia states. As the evDISCO approach circumvents the requirement of complex additional reporter lines (e.g. RiboTag or BioID), we expect that the planned PhD-project will rapidly provide deep insights into how microglia interact with neurons to co-define circuit function.