An initial series of studies will investigate basic physiological actions of norepinephrine (NE) and serotonin (5-HT) in the somatosensory and visual areas of the rat cerebral cortex. The goal of these studies is to establish a basis for assessing noradrenergic and serotonergic function in two animal models of epilepsy; cortically kindled and genetically epilepsy prone (GEPR) rats. Furthermore, tests used to examine biogenic amine function can be employed to clarify the mode of anticonvulsant drug action at synaptic levels within central neuronal circuits. In some cases, these same issues will be addressed using the cerebellar Purkinje cell as a model system for electrophysiological and neuropharmacological study. A combination of microiontophoretic techniques, stimulation of biogenic amine and synaptic afferent pathways and computer assisted analysis of peri-event histograms will be employed to quantitatively assess the effects of NE, 5-HT and several anti-epileptic agents on cerebellar and cerebrocortical neuronal responsiveness to synaptic inputs and putative transmitter substances. The primary concept to be tested is that NE and 5-HT exert modulatory influences on synaptic efficacy within target areas of the CNS. Specific studies in seizure prone animals will use the same protocols to assay for an alteration in cerebrocortical biogenic amine function which might correlate with increased susceptibility for convulsive episodes. Anticonvulsant drug effects on synaptically mediated and transmitter induced neuronal responses will be compared with NE/5-HT actions to determine if these compounds share in common, mechanisms to modify transmission of information through local brain circuits. Major new experimental strategies that have been developed include investigations of monoamine and anticonvulsant drug actions in awake, behaving animals and brain tissue slice preparations. The goal of studies in awake animals is to examine NE/5HT and drug effects under the most physiologically relevant conditions. In vitro studies employing extra and intracellular recording techniques offer the promise of revealing the mechanisms associated with monoamine and drug effects that are observed in vivo. Overall, the proposed research will contribute to a basic understanding of noradrenergic and serotonergic function in the cerebral cortex and cerebellum and clarify the role of these biogenic amines in seizure disorders and mechanisms of anticonvulsant drug action.
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