Nigel Bamford, MD is a pediatric neurologist and Assistant Professor in Pediatrics and Neurology at the University of Washington. The purpose of this proposal is to foster the scientific development and laboratory skills of the candidate. The technical skills acquired during this Award will contribute to the candidate's growth as an independent investigator. The objective of this proposal is to determine how the cerebral cortex communicates with the basal ganglia and how this process is altered in certain neurological diseases that affect dopamine (DA) transmission. The basal ganglia play an important role in voluntary movement and substance dependence. Excitatory glutamatergic corticostriatal projections from the cerebral cortex innervate the basal ganglia at the striatal medium spiny neuron (MSN), which also receives modulatory DA projections from midbrain nuclei. Both DA and glutamate (GLU) have been implicated in numerous neuropsychiatric disorders including Parkinson's disease and substance dependence. Using a newly developed imaging technique, the candidate has recently shown that DA depresses the release of GLU from a subset of cortical terminals providing filtering of cortical information to the striatum. The candidate hypothesizes that alterations in striatal DA release lead to long-term changes in striatal excitation mediated by DA-receptor hypersensitivity. There are three major goals: 1) Using mouse models for acute and chronic DA depletion, we will determine how DA receptors modify subsets of cortical terminals in the dorsal striatum, 2) we will determine how changes in pre-synaptic release are expressed post-synaptically, and 3) we will determine how methamphetamine sensitization and reinstatement affects MSN excitation in the ventral striatum. Our methods will utilize a novel imaging technique that allows direct visualization of activity from corticostriatal pre-synaptic terminals in murine striatal slice preparations. These optical studies will be integrated with whole-cell patch clamp recordings to precisely delineate the characteristics of the corticostriatal pathway and the effects of DA transmission at the MSN. The outcome of these investigations will demonstrate how alterations in DA release result in corticostriatal plasticity, and show mechanistically how certain neurological diseases cause aberrant striatal excitation. This project is expected to provide further insights into pharmacological alternatives for the treatment of movement disorders and addiction.
