Understanding the biological mechanisms of how pharmacologically-induced glucose dysregulation affects the brain and behavior

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Objectives:***It has traditionally been believed that brain activity controls peripheral glucose homeostasis to a greater degree than the other way around. However, recent evidence indicates that changes in glucose homeostasis can profoundly affect the brain and cognitive function. Our NSERC-funded research has demonstrated that atypical antipsychotic drugs (APDs), which are dopamine D2 receptor antagonists, reliably impair glucose homeostasis. This effect can be ameliorated by treatment with antidiabetic drugs. In a chronic study with the APD olanzapine, our rats displayed sustained loss of glycemic control over 9 weeks. Interestingly, the rats showed significant loss of hippocampal volume, which was partially reversed by daily exercise. There was a strong association between glucose dysregulation and smaller hippocampal volumes, indicating that chronic, uncontrolled, high levels of glucose may contribute to loss of hippocampal volume. ***Hypotheses:***Our main hypothesis is that APDs cause sustained glucose dysregulation, with a deleterious effect on the brain, resulting in hippocampal volume loss. We predict that this will be associated with significant cognitive impairment. We also predict that preventing glucose dysregulation will prevent these effects of APDs.***Research Plan:***1/ Firstly, we will determine the duration of volume loss in the hippocampus following chronic treatment with APDs in adult rats. We will assess whether there is a recovery of volume following different durations after termination of APD treatment. We will also determine if hippocampal volume is uniquely decreased by APD treatment, or whether additional brain regions show volumetric changes. Molecular substrates for volume loss will be examined.***2/ The cognitive effects of chronic APD treatment with associated glucose dysregulation will be determined. Following chronic treatment with APDs, drug-free animals or appropriate controls will be trained and tested on a hippocampal dependent behavioral task.***3/ We will confirm that volume loss and cognitive impairment caused by APDs is due to loss of glycemic control, rather than other mechanisms. Animals will be treated chronically with an APD and will be tested for hippocampal volume loss. Separate cohorts of animals will be co-administered antidiabetic drugs, which will decrease glucose dysregulation, which we predict will ameliorate the predicted loss of hippocampal volume.******Significance:***The present series of experiments will significantly extend our understanding of how pharmacologically induced modification of the peripheral regulation of glucose can alter the central nervous system at the level of the brain, with subsequent effects on behavior and cognition. The key biological pathways affected remain largely unknown, and the current studies will help to begin to understand the mechanisms that may be involved.********* **