Pause for thought: The role of corticostriatal circuitry and its dopamine innervation in the inhibitory modulation of associative learning

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The nuts and bolts of everyday thinking, provided by the formation of connections between related events, enable us to establish clear trains of thought. Associative learning mechanisms, common to all animals, support not only the cueing of thoughts, words and deeds, but also the ability to hesitate through the use of a 'mental brake' to suppress inappropriate thoughts and actions. When the ability to restrain the impulse generated by an association is lost, diverse symptoms may result. Clinically, impaired inhibitory modulation has been identified as contributing to a number of disorders, including addiction, anxiety, obesity and schizophrenia. Disinhibited behaviours are also a well-documented feature of the cognitive decline characteristic of normal ageing.Learning procedures developed in the laboratory rat provide an excellent model system to study the gating of unwanted associations. If a particular event predicts an outcome, learning is normally demonstrated by the animal's behavioural reaction to the first event. However, if the first event is presented in conjunction with another cue which means that the expected outcome will not now occur, the normal behavioural and cognitive reactions are inhibited. Impairments in such inhibition could explain a variety of symptoms, from over-eating when the consequences of eating more food will no longer be pleasant, to some of the disordered thought patterns identified with schizophrenia. We propose to use translational procedures in the rat, adapting the experimental design which we have used to test inhibitory learning in humans, in order to delineate the brain areas involved in inhibitory learning. The experimental brain treatments will be precisely targeted to areas known to be important for behavioural regulation and which receive projections containing the brain chemical dopamine implicated in the modulation of inhibitory learning. Highly controlled experiments of the kind proposed are necessary to identify the mechanisms underlying inhibitory learning deficits.We will (1) examine the effects of temporarily switching off small areas of cortex and interconnected areas (injecting a shortlived inactivating drug); (2) test for cross-talk in the patterns of electrical activity in interconnected brain areas; (3) use drug treatments to selectively manipulate the brain chemical dopamine, to determine the precise pathways through which inhibitory learning is modulated; and (4) examine how the observed behavioural effects depend on cross-talk between interconnected brain regions. The present project will advance previous findings in that we will selectively interfere with chemical signalling in specific brain pathways, by targeted drug delivery to areas first identified by temporarily inactivating small brain regions. One unique contribution of the present project will be the delineation of the role of the chemical modulator dopamine in the neural circuitry necessary for inhibitory learning. Other studies in our laboratory have shown that localised drug treatments with some selectivity to particular sites of action can have distinct effects on behaviour, often quite different to the effects of general brain damage in the same brain regions. Importantly, the behavioural procedures to be used in this project work in humans too; although the experimental details differ, there is sufficient similarity to translate findings from the animal laboratory to the clinic (and vice versa). Experiments in rats delineate the brain substrates of inhibitory learning and give vital clues as to where and how new treatments should work, with minimum side-effects.In parallel with the experimental programme, we will visit schools and use sixth form outreach programmes, as well as liaise with mental health professionals and contacts in the pharmaceutical industry, to explain the importance of animal work of this kind, and how it translates to our understanding of human health.