Cortical contributions to basal ganglia disorders

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

There is growing evidence that the basal ganglia participate in multiple 'loops' with a wide variety of cortical areas including regions of motor, premotor, prefrontal, orbitofrontal, cingulated, posterior parietal and inferotemporal cortex. These circuits could provide the basal ganglia with the neural substrate to influence motor, cognitive, emotional and perceptual domains of behavior. Likewise, abnormal activity in basal ganglia loops with the cerebral cortex could lead to a broad range of motor and neuropsychiatric symptoms such as those associated with Parkinson's and Huntington's Disease, L-DOPA toxicity, Tourette's syndrome, Attention Deficit Hyperactivity Disorder, Obsessive-Compulsive Disorder and depression. The overall goal of the experiments in this application is to link the specific motor and behavioral symptoms associated with basal ganglia dysfunction to the cortical areas that are responsible for their expression. To achieve this goal we will employ a unique multi-disciplinary approach. We will make microinjections of a GABAergic antagonist, bicuculline, into the external segment of the globus pallidus (GPE). These injections produce reversible dyskinesias, hyperactivity, attention deficits or stereotypes, depending upon the location of the injection site. We propose that the cortical area determines these symptoms, which is the target of the abnormal signals from the GPe. To begin to test this hypothesis we will locate the site in GPe where bicuculline injections produce hyperactivity. Then, we will use a novel neuroanatomical technique-transneuronal transport of rabies virus-to identify the cortical areas that are interconnected with this GPe region. Rabies virus is transported transneuronally in the retrograde direction through chains of synaptically-connected neurons (Kelly and Strick, '00, '03, '04). We will use transneuronal transport of rabies after injections into the hyperactivity site in GPe to define the cortical areas which are the source of input to this region of GPe. In a second set of experiments, we will use transneuronal transport of rabies after injections into the cerebral cortex to define the cortical areas which are the target of output from the hyperactivity site in GPe. Together these experiments should provide the 'proof in principle' that this two stage approach can be used to identify cortical areas that are responsible for the expression of motor and non-motor abnormalities associated with basal ganglia dysfunction. The results of these experiments should provide new insights into the functional neuroanatomy of basal ganglia disorders. As a consequence, our findings could stimulate new therapeutic approaches for dealing with complex problems like dopa-induced dyskinesias and the cognitive and emotional dysfunctions associated with Parkinson's Disease.