VTA IN COGNITION · Coordinated activity of midbrain dopaminergic neurons during cognition and in rodent models of schizophrenia

Final Activity Report Summary - VTA IN COGNITION (Coordinated activity of midbrain dopaminergic neurons during cognition and in rodent models of schizophrenia)

Brains are like orchestras. Both are subdivided into numerous, specialised sections with individual roles, yet the activity of all sections must be coordinated in order for the whole to function properly. Musicians in an orchestra keep time by following the lead of their conductor; by analogy, how do neurons of different brain regions coordinate their activity during the complex repertoire of behaviour? Electrophysiology allows us to record the electrical impulses through which neurons communicate. We find that many groups of neurons, like the sections of an orchestra, show rhythmic activity. Rhythms in connected neural networks are coordinated with one another, but only during behaviour that requires communication between the brain regions that contain them. Thus rhythmic activity can act as the brain's conductor, allowing different groups of neurons to communicate with one another at different times. This study will use recordings from three brain regions - the ventral tegmental area, the hippocampus and the prefrontal cortex - involved in learning and memory and decision-making to see how they interact during behaviour in rats. All three of the regions in question show signs of damage in schizophrenic patients. We suspect that the brain behaves like a 'cacophonous orchestra' during schizophrenia: a breakdown of coordinated timing leads to cognitive and behavioural abnormalities because different brain regions do not keep time with one another. We can model schizophrenia in rats and mice. For example, if we give animals drugs like ketamine (a drug of abuse sometimes called 'Special K') or PCP ('angel dust'), they develop behavioural problems like those in psychotic patients. By recording from the neurons of these animals, we can characterize the breakdown in coordinated neural activity that accompanies their breakdown in behaviour. Then, by comparing electrophysiology from these animal models with electrophysiology from the clinic (the impulses of human neurons can be recorded through the scalp as EEG, or 'brain waves'), we can begin to understand what goes wrong in the schizophrenic brain and, most importantly, begin to test therapies that will eventually put it right. This project has shown that a chemical called dopamine, released by neurons in the ventral tegmental area onto neurons in hippocampus and prefrontal cortex, is important for normal rhythmic activity in these brain regions. Dosing rats with ketamine causes excess dopamine release, and leads to abnormal rhythms in parallel with abnormal behaviour; these disruptive effects can be reduced by co-administering ketamine with a blocker of dopamine receptors. This work has initiated a number of studies aimed at understanding dopamine and related signalling in brain disease, and it is hoped that close collaboration with industry will lead to (a) more refined animal models of psychiatric disease and (b) future therapies to treat cognitive impairments.

Data: CORDIS, © European Union