Combined maternal immune activation and post-weaning social isolation of rats as an improved model of schizophrenia, to understand the neurobiology of the disorder and test potential new treatments

The Universities of Nottingham and Monash have launched a joint PhD programme at the cutting edge of molecular pharmacology and drug discovery and are recruiting exceptional calibre applicants of any EU nationality for a 4-year research programme including a full year of study at Monash University, Australia. Upon admission to the programme students would undertake 3 rotations from a bank of available projects prior to selecting a final project.

Schizophrenia is ranked as the third most disabling condition with a life-time risk of 0.5 to 1.0% and an estimated cost per patient to UK society in 1999 of £23K. Rearing rats in social isolation from weaning (to mimic early life social neglect) produces a robust set of lasting behavioural, neurochemical and neurostructural changes resembling many core symptoms seen in schizophrenia making this a very useful neurodevelopmental model to determine the neurobiology of, and potential new therapeutic treatments for, this disorder. A diverse array of evidence suggests that maternal exposure to infections during pregnancy is associated with a higher incidence of schizophrenia in resultant offspring. One hypothesis is that activation of the foetal immune system by elevated maternal cytokines may be the epidemiological link. In the rodent a similar maternal immune activation (MIA) can be evoked by the cytokine inducer polyriboinosinic–polyribocytidylic acid (Poly I:C), which mimics the acute response seen with a viral infection by inducing interferons and up-regulating pro-inflammatory cytokines in the dam and foetus. Poly I:C produces long-lasting changes in offspring behaviour which also resemble symptoms seen in schizophrenia. This study will combine MIA with subsequent isolation rearing as a ‘dual-hit’ to attempt to produce even more robust changes in behaviour which may have even higher translational relevance to changes reported in man.

Following MIA and isolation rearing or saline and group housing (controls) subjects will undergo a battery of behaviours (open field, novel object recognition, social interaction and reversal learning in visual touch screens). Particular focus will be paid to tasks having relevance to negative and cognitive symptoms of schizophrenia as these are the least responsive to antipsychotic medication. Deficits in social interaction (a paradigm thought to reflect negative symptoms in schizophrenia) are limited following isolation rearing alone and this study will also examine whether MIA causes more robust changes in this behaviour which would enhance the utility of the model for drug discovery. Western blots on selected post-mortem brain regions will measure marker of neurotransmission and cytokine levels will be detected by reverse-phase protein microarray and correlated with behaviour. Studies in second and third years will attempt to reverse changes by treatment with an existing antipsychotic, aripiprazole, and novel drugs under development.

This project will provide training in rodent behaviour, surgery, neurochemical analysis and benefit from a synergistic projects being undertaken by other postgraduates and post-doctoral fellows working in the group. The student would monitor changes in brain function during behaviour and following drug treatment; including measurement of core body temperature change by radiotelemetry and measurement of post mortem brain cytokine levels. This combination of techniques allows us to simultaneously relate changes in neuronal function to ongoing behaviours available to few research groups within academia in the UK. The project involves collaborate with a Monash laboratory involved in rodent neuropharmacology or drug discovery research where the molecular mechanisms of modulation of the dopamine D2 receptor by the drugs tested will be evaluated.

Applications consisting of a CV and covering letter should be sent to Professor Steve Hill ([Email Address Removed]) or Dr Ian Kerr ([Email Address Removed]).

Interviews will take place in Nottingham in person or via Skype as appropriate.