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Investigating brain network deficits in a rodent schizophrenia model

Principal Supervisor: Dr Todor Gerdjikov, Department of Neuroscience, Psychology and Behaviour

PhD Project Title: Investigating brain network deficits in a rodent schizophrenia model

Project outline:

Phencyclidine produces psychotic episodes in humans and phencyclidine administration in rats is used in research to study the mechanisms of schizophrenia. Rats treated repeatedly with phencyclidine show abnormal behaviours which are thought to reflect cognitive and negative symptoms seen in schizophrenia suffers. This is extremely important since negative and cognitive symptoms of schizophrenia are resistant to current treatments and are the major cause of disability among schizophrenia suffers. Available rodent models of negative/cognitive symptoms must therefore be studied with the aim of developing new treatments for this debilitating condition. We have carried out neurophysiological studies aimed at understanding the brain abnormalities seen in the phencyclidine model of schizophrenia (Asif-Malik et al., 2017, Young et al., 2015). We observed specific deficits in both the medial prefrontal cortex and in a brain network involving the medial prefrontal cortex and the nucleus accumbens.

The deficits in mPFC–NAc communication observed by us in the prefrontal-accumbal curicut may involve more distributed circuits involving potentially hippocampus. Ventral hippocampal and mPFC projections to NAc show complex interactions, which were compromised in another rodent model, the so-called MAM model, potentially involving ventral subiculum hyperactivity and mPFC hypoactivity (Belujon et al. 2014). Interestingly, ventral hippocampal hyperactivity, as found in the MAM rodent model of schizophrenia (Lodge and Grace 2007), is proposed to disrupt NAc responses, providing a potential mechanism for the reduced NAc firing observed by us (Asif-Malik et al., 2017). The MAM model results in some behavioral deficits which are similar to those reported in PCP-pre-treated rats, including impairments in reversal learning, and hypersensitivity to acute NMDA blockade (Belujon et al. 2014; Hradetzky et al. 2012). Here we will investigate how interactions between hippocampus and medial prefrontal cortex may mediate cognitive deficits in the phencyclidine model. We propose to simultaneously record electrophysiological activity in hippocampus and prefrontal cortex in rats trained in cognitive tasks and pretreated with phencyclidine. We will investigate whether PCP pretreatment will result in (1) hippocampal hyperactivity, and hippocampal-prefrontal desynchronization, and whether these effects will be more pronounced on trials where the animal shows lapses in attentional control.

BBSRC Strategic Research Priority: Molecules, Cells and Systems

Contact: Dr Todor Gerdjikov, University of Leicester