Biological rhythms and the dopamine system in cognitive dysfunction

Psychiatric disorders such as schizophrenia are associated with metabolic syndrome, obesity and diabetes. Schizophrenia affects 1.1% of the population and although not the most common psychiatric condition it is arguably the most severe and debilitating.

Sub-chronic administration of the NMDA receptor antagonist phencyclidine (PCP) in adult rats provides a good model of schizophrenia as it can induce a number of long lasting deficits (including behavioural, neurochemical and pathological deficits) in animals that mimic some key aspects of the disease (Neill et al., 2010). Cognitive deficits are recognised as being a core symptom of schizophrenia. The dopamine system is known to play a key role in cognitive dysfunction (Goldman-Rakic et al., 2004) and we have recently shown that sub-chronic PCP induces a cognitive deficit coupled with changes in the dopaminergic system (McLean et al., 2017). At the same time, the dopaminergic system is associated with circadian rhythms (Korshunov et al., 2017) which regulate brain centres important for affective, cognitive, and metabolic functions.

In mammals, circadian rhythms are regulated by the suprachiasmatic nuclei (SCN) in the hypothalamus. Animal models carrying mutations in genes that are involved in rhythm generation, so called clock genes, have been shown to induce behaviour analogous to psychiatric symptoms in humans (Landgraf et al 2014). These animal models also show symptoms of metabolic syndrome, obesity and diabetes (Barandas et al., 2015). Additionally, antipsychotic drugs used to treat schizophrenia, commonly cause metabolic adverse effects like hyperlipidaemia and weight gain, but metabolic imbalance can occur in patients independent of antipsychotic treatments (Harris et al., 2013).

Taken together these findings strongly suggest a link between biological rhythms, cognition and the dopaminergic system however the mechanisms underpinning this link are still unknown.

Hypothesis and aims

We hypothesise that the sub-chronic PCP model of schizophrenia will cause a disturbed pattern of clock gene expression which results in changes in the dopaminergic system in various brain regions (prefrontal cortex and hippocampus will be studied as areas of interest in cognition and know to be affected by the PCP model, the cerebellum will be used as a negative control region). This will fundamentally alter metabolic and cognitive function. To test this hypothesis, the objectives of this study are:

• To establish that cognitive dysfunction is induced by pharmacological manipulation in rats and to identify a link between cognition, metabolic function and synaptic densit
• To investigate circadian rhythms in the dopaminergic system in the brain
• To investigate the molecular mechanisms underpinning the observed changes