(MRC DTP) Hippocampal-prefrontal cortex network dysfunction in a neurodevelopmental model of schizophrenia

Drug discovery in schizophrenia is broken. Patients only have access to dopaminergic drugs from the 1950s that are ineffective for many and produce severe side effects in responders. Thus, there is a pressing need to develop novel therapies. Convergent lines of evidence implicate neuroinflammation in the aetiology of schizophrenia. In particular, infection during pregnancy that leads to maternal immune activation (mIA) is associated with increased risk of psychiatric illness in the offspring, starting at adolescence. Thus, an association between the early life environment and susceptibility to adult disease is now well established, however, the underlying mechanisms remain unknown.

Rodent models have been developed to study causal associations between mIA and neurodevelopmental disorders. These most commonly use the synthetic double-stranded RNA Poly (I:C) as a viral mimetic. This activates the maternal innate immune system, primarily through release of the pro-inflammatory cytokine IL-6. Our studies of behavioural changes from adolescence through to adulthood in the rat mIA model have revealed a robust cognitive deficit in the prefrontal cortex (PFC)-mediated translational attentional set-shifting task (ASST) that appears only at mature adulthood. This is accompanied by reduced parvalbumin (PV) expression in PFC. PV is the calcium binding protein located in fast-spiking GABAergic interneurons, which regulate gamma EEG oscillations and dependent cognitive function, all of which are also reduced in schizophrenic patients. In this project the student will analyse simultaneous intracranial spiking/local field potential-LFP-activity and surface EEG signals to assess changes in neural synchronisation between cortical and subcortical regions affected in schizophrenia (e.g. PFC, hippocampus, striatum, thalamus). In particular, this will incorporate for the first time a computational approach to measure how the amount and direction of information flow changes both within and between these brain regions in the mIA rat. The student will measure these changes during behaviour in both the ASST and other disease-relevant tasks (e.g., working memory) in the newly developed, touchscreen-enabled operant chamber. The latter uses an interface highly similar to that experienced by patients in the clinic, thus, providing a highly translatable link between this preclinical approach and patient care. In further studies, the student will test pharmacologically whether modulating IL-6 can reduce the severity of behavioural symptoms and underlying neuronal changes in the model. This project benefits from extensive training in key behavioural, in vivo physiological and mathematical techniques that are highly valued in both academia and the pharmaceutical industry.

https://www.research.manchester.ac.uk/portal/j.gigg.html
https://www.research.manchester.ac.uk/portal/joanna.neill.html
https://www.research.manchester.ac.uk/portal/m.montemurro.html
https://b-neuro.com/

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.