Exercise in the subchronic phencyclidine rat model for schizophrenia: mechanisms and effects on cognitive deficits

Abstract

Schizophrenia is associated with substantial cognitive deficits that dramatically reduce patients' quality of life. Now recognised as a core feature of the disorder, cognitive impairments best predict functional outcome. However, the drugs used to treat schizophrenia do not improve cognition, and many have cardiometabolic side-effects that contribute substantially to the reduced life expectancy of people with the disease. Drug development targeting cognition in schizophrenia to date has been unsuccessful. Non-pharmacological interventions to improve cognition, such as cognitive remediation therapy, have had limited success. Therefore, treatments to ameliorate the cognitive impairments in schizophrenia remain an urgent, unmet clinical need. Exercise has emerged as a potential intervention to reduce cognitive impairment in schizophrenia. While there is growing clinical evidence that exercise improves cognition, how it does so is poorly understood. Animal models are useful tools for investigating disease, and the subchronic phencyclidine (scPCP) rat model for schizophrenia is well-established and widely used to model schizophrenia-like cognitive deficits. However, research examining the effect of exercise on cognition in this model is lacking. This thesis presents a body of work examining the effect of voluntary exercise on cognition in the scPCP rat model for schizophrenia. The studies described within it demonstrate a novel exercise protocol can improve the novel object recognition (NOR) deficit present in this model. Furthermore, the pro-cognitive effects of wheel running endured for at least two weeks of sedentary behaviour but by four weeks, the NOR deficit had returned. Brain tissue was collected and analysed for synaptic and y-aminobutyric acid (GABA)ergic markers with western blotting. Two significant relationships were reported but these results were deemed inconclusive. Additionally, brain-derived neurotrophic factor (BDNF) was measured in plasma but no effect of exercise was found. For the first time, exercise was shown to improve cognition in the scPCP rat model for schizophrenia. Furthermore, this effect lasted for at least two weeks after exercise cessation. Pathological changes were not observed, but the robust behavioural changes produced will provide the opportunity to explore the pro-cognitive mechanisms of exercise in an animal model for schizophrenia.

Date of Award	21 Jul 2020
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stuart Allan (Co Supervisor), Alison Yung (Co Supervisor), Joanna Neill (Co Supervisor) & Michael Harte (Main Supervisor)