Rodent models of executive function

Rodent models of executive dysfunction, in particular schizophrenia, attempt to replicate in the rat certain features of clinical conditions for the purpose of testing hypotheses about the neural basis of the disorder and also for testing potentially therapeutic interventions. Frequently, models attempt to disrupt the neurochemical systems thought to be involved in the clinical disorder (most notably, the dopamine system in the case of schizophrenia). As such, they do not enable the testing of hypotheses about other neurochemical systems that might be involved. Furthermore, when it comes to identifying new treatments, the approach is dogged by circular reasoning. That is to say, an experimentally-induced increase in dopamine will lead to certain behavioural features and these are likely to be blocked by dopamine receptor blockade. As the blockade of dopamine receptors is one of the actions of neuroleptics (the classic treatment for schizophrenic symptoms), this approach can only tell us that a new compound is functionally similar to existing drug treatments. It is necessary to break out of this circle. Current drug treatments are quite effective in managing the positive symptoms of schizophrenia, but treatment of the associated cognitive and negative symptoms of the disorder is much less effective, using either pharmacological or behavioural intervention. This research project will take an entirely new approach to these problems and focus on the cognitive symptoms of schizophrenia. There is a cognitive profile in schizophrenia that might be characterized as inflexible, being both non-habituating and also less sensitive to requirements to change 'strategies' or rules. This latter is epitomized by the Wisconsin Card Sort Test in which patients are required to sort cards according to changing rules / and which schizophrenics and their close relatives do very poorly. An analogous test has been developed for the rat (Birrell and Brown, 2000) and, using this, it is now possible to measure this cognitive ability in rodents and identify its neural substrate. The areas of brain regions thought to be associated with the characteristic cognitive decline of schizophrenics are thought to be the orbital frontal cortex and the dorsal lateral prefrontal cortex, as previously modelled in rodents and monkeys (V.J.Brown, E.Bowman 2002; K.McAlonan, V.J.Brown 2003). We can now start to examine neurochemical interventions that modulate this cognitive ability. In the long run, it is hoped that this approach will lead not only to a greater understanding of the neural basis of complex cognitive function, but also will provide new insights that could lead to the development of improved strategies for drug discovery.