Pathways linking the midbrain tegmentum and basal ganglia have been long implicated in the control of movement. While it is suspected that pathologic involvement of these pathways accounts for some of the clinical signs of movement disorders, many of the basic features of their anatomical and physiologic relations to the basal ganglia have yet to be elucidated. This study will employ a correlated anatomical, neurochemical and physiological approach to determine the role of these connection in normal and pathologic movement in the primate. Our preliminary investigations in the rodent have localized a unique neuronal population in the midbrain tegmentum that is strongly interconnected with the basal ganglia (i.e., the midbrain extrapyramidal area, MEA). The topography and neurochemical identity of this cell group is distinct from that of surrounding neuronal subserves primarily motor functions. The first goal of this study is to provide a detailed characterization of midbrain efferents to the basal ganglia in the primate. We will determine the origin, neurochemical identity and synaptic termination of these connections. Immunohistochemical characterization of specific muscarinic, dopamine and glutamate receptor subtypes will serve to further differentiate these pathways from adjacent cell groups. The findings will provide a convectional and chemoarchitectonic map of the midbrain to guide the functional characterization of motor-related midbrain cell groups. The second goal of this study is to the define the motor functions of the MEA. Selective pharmacological activation or inactivation of this cell group will be performed in awake behaving monkeys so that its influence(s) on basal ganglia physiology and motor performance can be determined. In Parkinson's disease (PD) there is increased inhibitory output from the basal ganglia to the midbrain. We hypothesize that excessive inhibition of the MEA might be responsible for some of the motor symptoms of PD. The third goal of this study is to determine whether reversing this inhibition in monkeys made parkinsonian with MPTP will normalize the motor output of the basal ganglia and ameliorate the symptoms of PD. The results of these proposed studies will elucidate the neural and physiological substrates underlying the midbrain's mediation of motor behavior. They will also provide a better understanding of the pathophysiological basis for the presumed role of the midbrain in the motor dyscontrol of PD and in so doing identify a new potential target for the treatment of hypokinetic movement disorders.
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