The striatum is a key component of the basal ganglia, a collection of forebrain nuceli whose function is critical for the proper execution of voluntary movements. Normal striatal activity is regulated by the neuromodulator dopamine, and loss of dopaminergic inputs to the striatum results in the profound neurological impairments seen in Parkinson's disease. Nevertheless, despite numerous advances in understanding the contribution of dopaminergic signaling to striatal function, the precise mechanisms of dopamine's actions remain elusive. Dopamine is thought to influence the response of striatal neurons to synaptic inputs that target dendritic spines, small ~T micron protrusions of the postsynaptic cell membrane not easily studied by conventional electrophysiological methods. However, recent developments using optical imaging have enabled the study of neuronal activity at this small spatial scale. The specific goal of this work is to obtain a detailed understanding of how dopamine regulates synaptic transmission and integration in the striatum. In particular, the experiments will address two key questions. First, how does dopamine modulate the response of striatal neurons to excitatory synaptic inputs at the level of single synapses? Second, how does dopamine alter the ability of neurons to integrate spatially and temporally distributed synaptic inputs? To address these questions, a combination of electrophysiology and 2-photon laser scanning microscopy will be used to stimulate and record synaptic activity within individual dendritic spines. More generally, this proposal aims to provide new insight into the relationship between dopaminergic modulation and normal striatal activity. By expanding our knowledge of the interactions between transmitter systems in the striatum, these studies will enhance our understanding of the role of the striatum in behavior and contribute to the development of better models of Parkinson's disease and other movement disorders.
| Higley, Michael J; Gittis, Aryn H; Oldenburg, Ian A et al. (2011) Cholinergic interneurons mediate fast VGluT3-dependent glutamatergic transmission in the striatum. PLoS One 6:e19155 |
| Higley, Michael J; Sabatini, Bernardo L (2010) Competitive regulation of synaptic Ca2+ influx by D2 dopamine and A2A adenosine receptors. Nat Neurosci 13:958-66 |
| Higley, Michael J; Soler-Llavina, Gilberto J; Sabatini, Bernardo L (2009) Cholinergic modulation of multivesicular release regulates striatal synaptic potency and integration. Nat Neurosci 12:1121-8 |
