Inflammation in schizophrenia: mechanisms of negative symptom emergence, and contemporary therapeutic treatment

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The goals of this project are to:

• Obtain a mechanistic insight into perturbed brain cell development that occurs in schizophrenia through the utilization of ‘induced Pluripotent Stem Cells’ (iPSCs), with specific focus on potential dysfunction of astrocytes.
• Determine the contribution of astrocytes to inflammatory responses within the brain, and how this may be defective in schizophrenia pathology.
• Implement a regular exercise intervention into a first-episode psychosis (early schizophrenia pathology) population to investigate the anti-inflammatory effects of exercise.
• Assess whether regular exercise is a feasible intervention for reduction of negative symptoms in first-episode psychosis.

The details

Schizophrenia is a disease that is caused by alterations in genetic building blocks, as well as exposure to environmental stress that is experienced throughout development. This is suggested to cause the generation of a proinflammatory environment within the brain and central nervous system as well as the periphery, eventually leading to the presentation of specific types of symptoms. However, the types of brain cells that contribute to inflammation in schizophrenia, and how inflammation might cause eventual symptom presentation remains to be known. It is suggested that inflammation is relevant for the ‘negative’ symptoms in schizophrenia, which are broadly defined as a ‘loss of function’, including things like ‘lack of energy’, ‘lack of emotion’, and ‘lack of motivation’.

Therefore, within my PhD project I have first utilized ‘induced pluripotent stem cells’ (iPSCs) to model schizophrenia disease in a dish within a lab, in order to investigate the inflammatory changes that occur within the brain. iPSCs are a skin cell taken from a patient with disease, which is then reprogrammed and can be developed into any cell type, including brain cells. The important thing to note is that these cells carry the genetic parts of schizophrenia over, therefore when grown into brain cells in a dish, they grow similarly to how the schizophrenic brain would. This has enabled me to investigate how schizophrenia brain cells develop differently and investigate which contribute to the inflammation that is suggested in the schizophrenic brain. This research has shed light on a new found role for ‘astrocytes’ as important for inflammation.

After obtaining a mechanistic insight on inflammation in the schizophrenic brain, the second half of my PhD project is focused on using this knowledge to investigate how regular exercise might be useful for inflammation and negative symptoms that are experienced in schizophrenia. Engaging in physical exercise has various health benefits including weight loss, improved mood, but most importantly the release of anti-inflammatory factors into the blood which can travel through to the brain. This means that a period of regular exercise may be useful for counteracting the inflammation we see in schizophrenia, and could therefore effect the negative symptoms experienced. We aim to recruit a first-episode psychosis population (early schizophrenia) and conduct a 6-week exercise intervention. We will investigate different inflammatory markers in the blood to see if inflammation is reduced, as well as conducting symptom questionnaires to see how these anti-inflammatory changes may relate to symptom profiles.

Graduate researcher profile: Connor Dunleavy

What did you do before you started your PhD?

Before my PhD at the University of Birmingham, I completed an undergraduate degree in Sport and Exercise Sciences (BSc.) at the University of Birmingham, within the School of Sport, Exercise, and Rehabilitation Sciences. Following this, I stayed within the school to complete a Master of Science by Research (MSc by Research) with Professor Aldred, focused on inflammation in schizophrenia and how this may relate to specific symptom profiles.

What are the challenges of your research role?

Challenges of this research role include getting to grips with some of the most contemporary techniques within scientific research, for example culturing and developing induced pluripotent stem cells into functional brain cells.

I anticipate leading and running an exercise trial will also come with its challenges after previous experience on an exercise trial in first -episode psychosis. This can include maintaining high attendance levels, physical activity levels, and obtaining samples from psychosis cohorts.

What is the best part of your research role?

Supervision team

• The University of Melbourne: Professor Stephen Wood
• The University of Birmingham: Professor Sarah Aldred