Non human primate investigations into hippocampal-prefrontal interactions and cognitive dysfunction of relevance to schizophrenia

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Imagine if your world stopped making sense. You might see and hear strange things. You might change what you remember, the decisions you make, and your enjoyment in things. These are all symptoms of schizophrenia (SZ), a devastating, incurable psychiatric illness affecting 1% of humans. Current medicines are effective at treating some symptoms - particularly the auditory, visual and belief changes (the "positive" symptoms). However the problems with decision making, memory and mood (the cognitive and "negative" symptoms) are poorly understood, and hence poorly treated. Our research aims to understand the causes of the cognitive symptoms, and to suggest treatments.SZ is not easy to study in animals. It is hard to know if an animal is hallucinating. However, we know things about "positive" symptoms in humans that we can test for in animals. For example, these symptoms are associated with the release of too much dopamine (DA) in the striatum, a brain region that governs motivation and movement. Humans with SZ also have changes in their prefrontal cortex (PFC) and hippocampus, two connected structures which may be responsible for some of the cognitive symptoms. To investigate these symptoms we can measure behaviours that go wrong in SZ.These studies are often performed in rats, but rat PFC isn't like human PFC as it's much simpler. In between rats and humans are small monkeys like marmosets. We can measure complex behaviours in marmosets (such as working memory for things they've seen) that depend on the same PFC subregions as in humans, and we can also measure neurotransmitters in the PFC, and cause changes to brain regions in experiments that couldn't be performed in rats or humans.Humans with SZ also show alterations in a structure called the perineuronal net (PNN), a scaffold for brain cells in both the hippocampus and the PFC. We know that rats who have their hippocampal PNN removed show changes in DA like those seen in SZ. Therefore it may be that hippocampal changes, caused by the loss of the PNN, in turn cause changes in the PFC that are responsible for the cognitive symptoms of SZ. Our preliminary data supports such a link. If so, this might suggest a new way of treating these symptoms. We therefore plan to degrade the PNN in the hippocampus or PFC of marmosets by injecting a PNN-degrading enzyme. We'll measure what this does to PFC structure, chemistry (levels of signalling chemicals), and function, and we will include appropriate control conditions (e.g. to make sure that an injection itself isn't what's important). We will do this using imaging techniques such as magnetic resonance imaging, positron emission tomography, and by sampling fluid directly from the PFC. We will measure the function of PFC regions through tasks we've developed (and are developing) that depend on specific PFC regions, like tests of working memory (which tax the dorsolateral PFC) or the ability to abandon a previously rewarded stimulus when another comes to predict reward better (which requires the orbitofrontal PFC). For comparison we will also investigate the effects of degrading the PNN in the dorsolateral PFC. We will then relate changes in activity, structure and chemistry to changes in behaviour. We are very experienced in this research. We look after our marmosets exceptionally well and don't use more than we have to.We predict that hippocampal PNN degradation will affect PFC function, and we will then use what we learn about the changes in PFC chemistry to try to treat any behavioural problems caused by PNN degradation, at first by giving "rescue" drugs into the PFC directly. These studies might lead to new tablets for cognitive symptoms in SZ.