Research Interests:

Our main research is concerned with mechanisms of synaptic plasticity. To investigate morphological and ionic mechanisms of changes in synaptic strength that may subserve memory, we are developing and applying optical methods with high spatial and temporal resolution. Using confocal and multiphoton-excitation laser-scanning microscopy in conjunction with in vitro brain slice electrophysiology, intravital staining techniques, computational volume reconstruction and morphometry, we are studying changes in the function and structure of individual dendritic spines and synaptic terminals in living hippocampal tissue during long-term potentiation, a widely-used model of learning and memory. To study possible potentiation-induced changes in evoked pre- and postsynaptic calcium and voltage fluxes, we have developed a sensitive ratiometric fluorescence CCD imaging system capable of monitoring cellular voltage and ion transients at more than 2500 images per second; we are using this system and the laser- scanning methods, together with appropriate fluorescent indicators, to investigate patterns of activity- dependent ion fluxes in organotypic hippocampal monolayers. We are now combining these optical techniques with transgenic and antisense oligonucleotide methods, to probe the involvement of specific genes in neuronal development and plasticity.

In related studies, we are investigating the mechanisms of dendritic and axonal morphogenesis. We have developed a quantitative physical theory describing the control of cell growth by diffusible morphogens, that accounts for the formation and variation of dendritic morphologies and for the differentiation of axons. We are now testing the theory by comparing the computed growth of model cells with the growth of real neurons under a variety of imposed conditions in vitro. We are investigating the involvement of these hypothesized mechanisms in the establishment of thalamocortical connections in vivo, and will study their involvement in dendritic remodelling with aging, stress and injury.

Other research in my laboratory is concerned with mechanisms and therapy of Parkinson's and Alzheimer's diseases. In our clinical trial of fetal neural transplantation for therapy of Parkinson's disease, five patients received dopaminergic transplants and have been monitored untensively for over three years with functional and cognitive testing and fluorodopa PET imaging. In related laboratory studies, we have developed means for long-term in vitro propagation of undifferentiated, proliferating human central nervous system stem cells. We have also been developing rodent and primate models of senescent dementia and Alzheimer's disease, studying the role of cholinergic deficits in cognitive deficits, examining the ability of fetal cholinergic transplants to improve cognitive function, and investigating the cellular mechanisms of age-related cognitive impairment.