Preclinical studies ask how sex steroid-related, dopamine-related (and other neurotransmitter systems) and immune-related gene and protein expression in the nigrostriatal, mesolimbic and mesocortical dopamine pathways are altered in the rat maternal immune activation (MIA) model of dopamine dysregulation in offspring with high and low inflammation. We can measure inflammatory molecules and sex steroids in the periphery and relate this to behaviour and to gene and protein expression in different brain regions. We can also do this in both sexes and longitudinally (i.e juvenile, adolescence, adulthood, aged). It is unknown whether schizophrenia patients move in and out of high inflammation status and how this relates to cognitive decline and psychotic episodes or how it is related to antipsychotic treatments or if it changes with changing circulating hormone levels. I will address these questions in the MIA model.

Significance: Understanding sex steroid-induced schizophrenia-related behaviours in the context of neuroinflammation and the dopamine neurotransmitter system in midbrain, cortex and striatum in both sexes will provide new knowledge that will lead to new treatment targets with a focus on individualized treatment (i.e. by sex and inflammatory status).

Post mortem Human brain Studies

The midbrain, although critical to dopamine regulation is surprisingly understudied in the context of schizophrenia, especially in the post mortem field. We use post mortem human midbrain from people that had schizophrenia during their lives and compare them to brains from people that had no neuropsychiatric diagnoses. Our research has identified dysregulation of multiple DA-related transcripts (Purves-Tyson, Translational Psychiatry 2017) and high and low immune groups in this cohort (Purves-Tyson, Molecular Psychiatry 2021, online 2019). As I identify further molecular targets in the MIA model, these will be interrogated in the schizophrenia midbrain cohort.