EXCEED THE SPACEPROVIDED. The role of the substantia nigra (SN) superior colliculus (SC), subthalamic nucleus (STN), and parabrachial nuclei (PBN) will be investigated as substrates for GABA-mediated seizure control in rodents and primates. Focal nicroinjection of GABA agonists, GABAelevatingagents and GABAantagonists will be used to identify specific ;ubregions of the SN, SC, and PBN which exert seizure regulatingeffects in models of complex partial and generalized convulsive seizures. Special emphasis will be placed on age-related changes in site-specific seizure control todetermine whether GABA receptor-mediated anticonvulsant actions change during development. Site-specific microinjection of irugs into discrete brain areas will be used to reveal the function of GABA transmission in the regions of interest. In iddition, behavioral and anticonvulsant effects of clinical Deep Brain Stimulation (DBS) applied to SN and STN of the jrimate will be evaluated and compared with the effects of the GABAergic drugs. Measurements of neurological unction, includingbehavioral and electroencephalographicanalyses, will be performed. An important goal of the proposed studies is to evaluate observations made in rodents for their relevance to primates, rhus, primates will be tested for the effect of treatments that have been demonstrated to be therapeutic in rat modelsand hese will be compared with treatments under experimental investigation in human patients. Furthermore, the functional elationship between the STN and the SN in the primate will be studied in the context of effects on posture,movement, rnd seizures. The following hypotheses will be tested: )GABA-mediated anticonvulsant effects evoked from theprimate SNare regionally specific and will be reproduced by DBSin SN, 2)Disinhibition of the deep SCof theprimate is mticonvulsant, 3)GABAergicinhibition in the lateral PBN is anticonvulsant in the rodent, and is a component of the -.ircuitry mediating the anticonvulsant actions ofSN, 4) Disinhibition of the STNof theprimate is anticonvulsant(in contrast to rat in which inhibition of STNis anticonvulsant); DBSin STNwill evokean anticonvulsant action by enhancing the actvity of GABAergic inputs to SNin theprimate. These studies will help to elucidate the neural circuitry hat contributes to seizure resistance in the brain, and to identify mechanisms to enhance that circuitry. By using juvenile md adult animal models of complex partial seizures and making cross-species comparisons, the studies will contribute to :he development of novel therapeutic strategies for drug-resistant epilepsy. ' PERFORMANCE SITE ========================================Section End===========================================
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