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The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on March 19, 2010). Thesis advisor: Dr. Steven A. Hackley. Includes bibliographical references.

Ce mémoire traite de l’organisation anatomique et fonctionnelle de la voie corticosubthalamique chez le singe macaque. Cette projection neuronale, aussi connue sous le nom de voie hyperdirecte, a été étudiée grâce à une méthode de marquage neuronal unitaire. L’injection d’un traceur antérograde, la biotine dextran amine, dans la couche V du cortex moteur primaire de quatre singes cynomolgus (Macaca fascicularis) par microiontophorèse nous a permis de tracer en détails l’arborisation axonale de 28 axones corticofuges composants la voie hyperdirecte. Les principaux résultats de cette étude montrent que la projection corticosubthalamique est essentiellement ipsilatérale et que la population de neurones à l’origine de cette projection est indépendante de celle composant la voie corticostriée. Après avoir quitté le cortex, les axones de fort calibre (jusqu’à 3.7 μm de diamètre) de la voie hyperdirecte voyagent le long de la capsule interne jusqu’au tronc cérébral. À la hauteur du noyau subthalamique, ces axones émettent des collatérales de plus petit diamètre qui innervent non seulement le noyau subthalamique, mais également la zona incerta, le noyau rouge, les noyaux pontiques supérieurs et le noyau réticulaire du thalamus. Dans le noyau subthalamique, les fines collatérales de la voie hyperdirecte s’arborisent profusément au sein du territoire sensorimoteur. Les résultats obtenus dans le cadre de la présente étude par marquage neuronal unitaire révèlent, pour la toute première fois chez le singe, que la voie « hyperdirecte » est majoritairement « indirecte » puisque celle-ci provient essentiellement de collatérales d’axones principaux qui innervent les étages inférieurs du tronc cérébral. En outre, cette projection ne semble pas exclusive au noyau subthalamique puisque les axones qui la composent ciblent plusieurs autres régions motrices cérébrales. / This thesis deals with the anatomical and functional organization of the corticosubthalamic pathway in macaque monkey. This neuronal projection, which is also known as the hyperdirect pathway, was investigated with the help of a single-cell labeling method. An anterograde tracer, biotin dextran amine, was microiontophoretically delivered in layer V of the primary motor cortex in four cynomolgus monkeys (Macaca fascicularis), allowing us to trace in detail the axonal arborization of 28 corticofugal axons forming the hyperdirect pathway. The main results of this study indicate that the corticosubthalamic pathway is essentially ipsilateral and that the population of neurons at the origin of this projection is distinct from those giving rise to the corticostriatal projection. After leaving the cortex, the large caliber axons (up to 3.7 μm in diameter) that form the hyperdirect pathway travel along the internal capsule, heading toward the brainstem. At the subthalamic nucleus level, these axons emit some small-diameter collaterals that innervate the zona incerta, the red nucleus, the superior pontine nuclei, the thalamic reticular nucleus, and the subthalamic nucleus. In the latter structure, thin collaterals of the corticosubthalamic projection arborize principally within its sensorimotor territory. The results of the present single-axons tracing study reveal, for the very first time in primates, that the so called “hyperdirect” pathway is largely “indirect” since it is mainly composed of collaterals of main axons that travel downward to the brainstem. Moreover, this projection does not seem exclusive to the subthalamic nucleus since it targets several other cerebral motor nuclei.

The consequence of many psychiatric and neurodegenerative disorders, such as Parkinson's disease and schizophrenia, is an impairment in ‘executive functioning'; an umbrella term for several cognitive processes, including the focussing and shifting of attention and the inhibition of responding. The ability to form an ‘attentional set' involves learning to discriminate qualities of a multidimensional cue, and to subsequently learn which quality is relevant, and therefore predictive of reward. According to recent research, the subthalamic nucleus (STN) and possibly the adjacent zona incerta (ZI) may mediate the formation of attentional set. Dysregulation of the STN as a result of Parkinson's disease contributes to characteristic motor symptoms, and whilst deep-brain stimulation of this region may treat gross motor impairments, it may also impair cognition. The work in this thesis aimed to expand our understanding of the mechanisms of attentional set-formation, and the role of the STN in this process. This thesis evaluates new methods for examining set-formation in the attentional set-shifting task; rather than inferring this behaviour solely from the cost of shifting set, modifications to the task design in Chapters 3 & 4 explored several hypotheses designed to exploit a deficit in this behaviour. Chapter 6 revealed that inhibition of this region with designer receptors leads to a disruption in attentional selectivity, which compromises the ability to form an attentional set. This manifested as an inability to parse relevant information from irrelevant, and instead, animals learned the stimuli holistically. The findings in this thesis also suggested that reversal and attentional shifting processes do not operate independently, but rather in a hierarchy, and that consequently, the STN is a region that may be crucial in selecting appropriate responses during associative learning that leads to the formation of an attentional set.

Lesions of the subthalamic nucleus (STN) alleviate the cardinal signs of idiopathic as well as MPTP-induced Parkinson's disease in primates. For this reason, the STN is a target for clinical treatment of Parkinson's disease using deep brain stimulation. Despite its small size, the STN plays a vital role in the cortico-basal ganglia-thalamic network. However, the functional features of the STN have yet to be fully uncovered. The research presented in this thesis examines the functions of the STN by measuring behavioural changes resulting from STN lesions in rats performing executive abilities. In the first experiment, a ‘signal change' reaction time task was developed and the performance of humans and rats was compared. The main findings were that although humans and rats used different strategies in the task, the task did challenge the ability to inhibit unwanted responses. In the second and third experiments, the effects of bilateral lesions of the STN on performance of two variants of the ‘signal change' task were examined. Rats with the STN lesions were able to inhibit responses when under stimulus control, but were less able to inhibit responses that were not under stimulus control. In the final experiment, the effects of lesions of the STN on inhibitory control in a nonmotor, cognitive domain were examined. Rats with STN lesions were not impaired on reversal learning, suggesting intact inhibition of previously rewarded responses. The rats with STN lesions did show impairments in selective attention which resulted in an inability to form an attentional set. Together, these findings challenge the conventional view that the STN simply plays a global inhibitory role. Rather, the contribution of the STN to inhibitory control is more complex and neither the motor nor the cognitive effects of the lesions are easily explained simply as a failure of inhibition.