Neurochemical and Neuroanatomical Basis Of Reversal Learning In The Rat

The aim of this thesis was to investigate the neural and neurochemical substrates of cognitive flexibility using a novel touchscreen task involving serial reversal of visual discrimination in rats. Much evidence has implicated frontostriatal circuitry in the mediation of reversal learning and this thesis sought to further delineate the role of these structures. Although dopamine has been implicated in cognitive flexibility in psychopharmacological studies in primates, there are relatively few studies in the rat. Consequently, the behavioural effects of a dopamine D2/D3 receptor antagonist (raclopride) were assessed, both systemically and via intracerebral infusions into different regions of the striatum. Systemic raclopride had no specific effects initially on serial reversal learning, but continued treatment with a low dose did impair retention of a novel visual discrimination, and its subsequent reversal. Intracerebral infusions of raclopride into the dorsomedial and dorsolateral striatum produced a dissociation during separate phases of reversal learning, dorsomedial infusions affecting new learning, and dorsolateral infusions producing perseveration in the early phase. By contrast, raclopride infusions into the anterior dorsomedial striatum produced a general slowing of responding, whereas infusions into the nucleus accumbens core region had no significant effects. The second part of the thesis investigated the role of prefrontal cortical projections to the striatum in serial reversal learning, focusing on the lateral and medial orbitofrontal cortex, as well as regions of the medial prefrontal cortex. Local temporary inactivation of these structures via infusion of a muscimol/baclofen mixture produced dissociable effects. Inactivation of the infralimbic cortex led to a significant general improvement in reversal learning regardless of phase, while inactivation of the medial orbitofrontal cortex led specifically to a significant reduction in the number of errors during perseveration. By contrast, inactivation of the lateral orbitofrontal cortex caused a significant increase in the number of errors and omissions during perseveration, whereas prelimbic cortex inactivation had no major effects. The findings of the thesis are discussed in terms of the separate roles for the different phases of reversal learning of different sectors of the frontal lobe and striatum in the rat, and the modulatory role of the striatal D2/D3 receptors. Possible clinical, as well as functional, implications of the results are also considered.BBSR