The ultimate objective of the proposed research is to provide clinicians with data and techniques requisite for the implementation of transplantation of neural tissue in the treatment of Huntington's Disease (HD).
Specific Aim 1 will address whether transplanted cells can ameliorate the cognitive deficits associated with HD. We will assess this using delayed alternation and spatial learning and memory tests pre- and post-transplantation in a rat model of HD. These measures will be correlated with graft growth, survival, and the neurochemical phenotype of the grafts to identify graft characteristics which are important for recovery of cognitive function. Transplant efficacy must be assessed in an animal model evolutionarily more closely related to humans in order to test more complex behavioral measures and to evaluate the clinical applicability of the procedure.
Specific Aim 2 addresses these issues in a non-human primate model of HD. Cells will be transplanted into rhesus monkeys with 3-nitropropionic acid lesions of the caudate and putamen. Monkeys will be tested behaviorally pre- and post-transplantation by videotape assessment of incidence of choreiform movements, orofacial dyskinesia, dystonia, and manual dexterity. Further tests will be conducted to assess cognitive effects, including passive avoidance and visual discrimination tasks. At the end of the behavioral testing the animals will be sacrificed and their brains removed for histological processing. Growth and survival of the graft, as well as its cellular phenotype, will be correlated with behavioral data to evaluate graft efficacy and potential for clinical application. Clinically, one of the most important weaknesses of cell transplantation procedures is the absence of a reliable method for monitoring graft development.
In Specific Aim 3, tissue grafts in rats and monkeys with excitotoxic striatal lesions will be monitored using 1-H nuclear magnetic resonance spectroscopy (NMRS) which utilizes MEGA, a frequency selective refocusing technique, to monitor GABA levels in vivo. In simultaneous experiments, rats with intrastriatal lesions and grafts will be monitored using NMRS. The striata of rats will be imaged/measured using the 9.4 Tesla magnet pre- and post-lesioning. Volumetric, morphologic and immunohistochemical measures will be taken periodically and correlated with the values obtained from the imaging studies and with behavioral measures from each rat.. The imaging data will be correlated with the final histological and behavioral measures obtained from the primate subjects at the end of the experiments to evaluate the clinical efficacy and applicability of this NRMS technique in tissue transplantation.
