Description of the thesis topic

This PhD project is part of a collaboration between Imperial college London and CNRS over the development of a multi-modal, microengineerined diagnostics platform for detecting depression and evaluating treatments. Diagnosis and treatment of depression are imprecise, and antidepressants have variable efficacy. To meet the critical need of diagnosing and treating depression, we must better define the chemical basis of this illness in humans. A critical step towards this goal is to identify and measure depression biomarkers in human models and assess their response to antidepressants. There are three main theories of depression. The monoamine theory states that the levels of serotonin are lower during depression. The plasticity theory postulates that low glutamate levels underlie a loss of a neural connections. Finally, the inflammation theory hypothesizes that inflammatory molecules such as histamine and nitric oxide (NO) drive functional changes in the brain that lead to depressive behaviour. The collaboration proposes to bring together serotonin, histamine, glutamate and NO sensors for a proof of principle device providing the first chemical test for depression.
This PhD project will develop glutamate and NO electrodes compatible with this 4-pronged device. Probes for NO and glutamate will be based on carbon-fiber microelectrodes (CFMs). For NO detection, CFMs will be coated with fluorinated xerogel and polyurethane as an outer protective layer against biofouling. Glutamate sensors will be obtained from platinized carbon fiber microelectrodes covered with the enzyme glutamate oxidase. These electrochemical sensors will oxidize NO and glutamate and provide an estimation of their ambient concentration based on the intensity of the oxidation current. After characterizing the performance of NO and glutamate probes in standard solutions, they will be implanted in the brain of anesthetized rats in a paradigm of cortical spreading depolarization (SDs), waves of near-complete depolarization of neurons and glial cells that propagate through the cortex and evoke large glutamate and NO release. Glutamate and NO sensors will also be implanted in the brain of anesthetized rats subjected to carotid artery occlusion to mimic brain ischemia, and during an episode of brain inflammation triggered by lipopolysaccharide, a pro-inflammatory bacterial extract. This in vivo task will not only validate the use of the new sensors in a living system, but also further our understanding of the pathophysiology of glutamate and NO release during brain injury and neuroinflammation. For the final phase of the project, the PhD student will go to Imperial and insert glutamate and NO electrodes into a 4 electrodes system also equipped with serotonin and histamine electrodes. The 4 measurements will be applied to neural spheroids made of human derived iPSCs in control and under inflammation conditions. This four-pronged probe will also be tested in Lyon in animal models of inflammation, allowing us to assess whether the ex vivo model can recapitulate the in vivo signals.
This project will create the first probe capable of measuring serotonin, histamine, glutamate and NO in human-derived organoids or in the brain of animal models of inflammation. We expect that this new technology will lead to a new understanding of the biochemical mechanisms of depression, diagnosing depression and screening novel drugs. Chemical measurements of depression do not exist, and the sensors developed here will be first in their class. Their impact in brain research and pharmaceutical research should be large, affecting the lives of millions of patients in the long term.

Work Context

This project is a collaboration between the TIGER (Translational and Integrative Group in Epilepsy research) team at the Lyon Neuroscience Research Center (CRNL) and Prof. Parastoo Hashemi's laboratory in the Department of Bioengineering at Imperial College London. The PhD student (M/F) will be administratively attached to the CRNL but will be supervised by Stéphane Marinesco and Parastoo Hashemi on a co-supervision basis. Missions to London are planned for the second half of the PhD. Both CRNL and Imperial laboratories are centers of excellence in the field of brain-implantable chemical microsensors, developing innovative approaches for detecting neurotransmitters and metabolites in the brain or in cell cultures. In addition, both laboratories have excellent infrastructures for animal experimentation, microscopy and cell culture.

Constraints and risks

Handling of live animals (rats)
Possible handling of toxic chemicals.