Angela L. Holmes, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The basal ganglia circuitry is critical for control of posture, motor coordination, initiation of behavior and procedural learning and memory (1).Dysfunction within the basal ganglia circuitry results in disorders that involve motor abnormalities. Motor abnormalities stemming from the pathology within the basal ganglia have been the hallmark of Parkinson's disease {PD) and Huntington's disease (HD). Understanding the clinical problems of PD and HD is of high priority because of the progressive neurodegenerative nature of both disorders and the serious disruption they have on everyday lives of the patients and their family members. My main interest is to advance the understanding of the neural substrates underlying some of the clinical symptoms of PD and HD. I will focus my project on the motor abnormalities evoked from one of the principle output structures of the basal ganglia, the substantial nigra pars reticulata (SNpr), and one of its principle target regions, the deep layers of the superior colliculus (DSC). Better knowledge of the neural mechanisms and pathways responsible for the motor abnormalities will be important for developing better therapeutic strategies for both disorders and for minimizing side effects of therapies for PD. Our preliminary results in the nonhuman primate showed that motor abnormalities (some of which are not seen in the rat) are elicted by either inhibition of SNpr or disinhibition of the DSC. Although the role of DSC in the regulation of posture and motor behavior has been well documented in the rat, little information exists about the function of this region in the nonhuman primate. In addition to the motor abnormalities, PD and HD patients may also experience disruption in their emotional states (7-12). It is possible that these emotional disturbances (e.g., depression) could at least in part be due to the abnormal functioning of the circuitry that involves DSC. Rodent literature identified DSC as a part of the "defense system" (13-18) but a similar role for DSC has not been established in the primate. Preliminary data from our lab clearly showed in the nonhuman primate a role for DSC in the production of emotional responses. However, it is not known whether, similarly to motor behaviors, DSC influence on defense-like emotional responses is under basal ganglia control. Therefore the following specific aims are proposed: Specific Aim 1: Characterize the motor abnormalities elicited from DSC and SNpr. Specific Aim 2: Determine whether the DSC mediates the motor abnormalities evoked from SNpr. Specific Aim 3: Determine whether the SNpr has modulatory control over the defense-like emotional responses. These aims will be accomplished by manipulating DSC and SNpr by enhancing or reducing their activity using the GABA-A antagonist bicuculline or the GABA-A agonist muscimol, respectively. [unreadable] [unreadable] [unreadable]