Neural and neurochemical mechanisms of sustained visual attention

Abstract

This thesis investigates the neural basis of attentional control, in the rat, especially in terms of the role of the midbrain dopaminergic systems using behavioural, pharmacological, neuroimaging and neurochemical methods. A visual discrimination task was developed for measuring sustained attention. To this end, brief visual signals over signal omission had to be detected and novel manipulations of visual distraction were developed. Particular emphasis is placed on individual differences in performance, which is of importance in determining the effects of systemic or intracerebral administration of a number of drugs affecting the central catecholaminergic systems. The technique of in vivo fibre photometry is used to quantify dopamine release during sustained visual attention. Overall, the results are interpreted in terms of various behavioural constructs, which are influenced by dopamine fluxes during performance of the attentional task. The general Introduction in Chapter 1 provides a review of the relevant literature concerning current knowledge of neurochemical modulation in attentional control and its relevance for human studies including clinical disorders. Chapter 2 describes the general methods used. The signal detection task (SDT) used to measure sustained visual attention is described in detail together with the methods used in training food-deprived rats to acquire and perform the task in a consistent manner. Surgical procedures used for microinfusions and fibre photometry are also outlined. Chapter 3 provides a comprehensive validation of the SDT as a measure of sustained attention and documents naturally occurring individual differences in performance. Subjects could be divided into low or high-attentive subcategories differing only in visual detection, but not in terms of positional or yes-no bias, movement speed or motivation. Two distinct types of behavioural challenges were developed to enhance attentional load, specifically visual distraction and brief visual signal durations. Chapter 4 assesses whether these individual differences are the result of system-wide volumetric or connectivity variations. No system-wide differences in brain volume were observed, suggesting that a more delicate process gives rise to individual variability. Chapter 5 used fibre photometry to obtain sub second live dopamine signalling with dlight1.3b in the nucleus accumbens core during SDT performance. There were distinct dopamine signalling transients during different phases of performance. These were interpreted to reflect possible roles for mesolimbic dopamine in reward prediction during trial initiation and the subsequent attentional orienting response to both visual signal and its omission and trial outcome (reward or its omission). Furthermore, some transients could be interpreted as anticipatory responses that appeared to represent confidence in choice outcome. Upon introducing either a behavioural challenge, the dopamine signalling transients were altered in such a manner to suggest modulation of reward prediction errors. In Chapter 6 the effects of systemic administration of amphetamine on SDT performance were determined. Amphetamine, an indirect catecholamine agonist, that enhances dopaminergic transmission, improved accuracy in low-attentive subjects, whilst impairing high-attentive subjects. Dopamine signalling transients showed a disruption of dopaminergic signalling at trial initiation, during the orienting response and reward anticipation, which were comparable to the behavioural effects of visual distraction. Chapter 7 compared the effects on SDT performance of two agents with different actions on catecholaminergic systems, systemic methylphenidate and atomoxetine. Their distinct effects were modulated by individual differences, as shown in low-attentive and high-attentive rats, suggesting different roles of dopamine and noradrenaline in SDT performance or, alternatively in cortical and subcortical dopamine function. Systemic effects of a Dopamine 1 (D1R) and Dopamine 2 receptor (D2R) agonist were also determined for comparison with the intracerebral administration in Chapter 8. Chapter 8 determined the regional effects of D1R and D2R agonists by microinfusion into the nucleus accumbens (shell or core) and the medial prefrontal cortex. The D1R agonist improved, whereas the D2R agonist impaired performance in the medial prefrontal cortex. However, in the nucleus accumbens core, D1R and D2R agonists impaired performance, thus demonstrating distinct effects of dopamine receptor subtypes in cortical and subcortical brain regions. Chapter 9 summarises and discusses the general findings and their theoretical and clinical implications for understanding the extensive and distinct roles of central dopaminergic systems in regulating attentional control.