Current Research Description
My laboratory is interested in understanding how addictive drugs progessively alter the molecular and cellular make up of specific neural circuits to sustain the development of compulsive addictive behavior. We are focused on the actions of nicotine as a model for understanding mechanisms underlying CNS plasticity and for understainding mechanisms that serendipitously enhance the ability of the CNS to withstand neurotoxic insults characteristic of neurodegenerative diseases.
Nicotinic acetylcholine receptors (AChRs) are the primary mediators of the actions of nicotine in tobacco in the CNS. Neuronal AChRs are ion channels assembled from multiple alpha and beta subunits that are associate with distinct sets of cytosolic proteins of different functions, only a few of which have been identified to date. Some of these cytosolic proteins transiently associate with AChRs and regulate their assembly, trafficking, and turnover, whilst others cluster AChRs at membrane microdomains and/or serve as scaffolds for the assembly of signaling complexes that couple channel activity to specific intracellular signaling cascades.
Because the changes in the properties of neural circuits supporting addictive behavior, much like those underlying memory and learning, are initiated by dynamic and highly orchestrated changes in the density, functional organization, and properties of channels and receptors, it is likely that AChR associated cytsolic proteins, and the processes they regulate, participate in effecting these changes following repetitive activation of AChRs by nicotine. These changes in AChRs then lead to downstream adaptive changes in neural networks within which they are expressed to change their emergent functional properties. My laboratory has identified proteins involved in regulating AChR assembly, trafficking, turnover, synaptic targeting and signaling. We are also studying the roles of these proteins in mediating AChR dysfunctions in animal models of schizophrenia, nicotine dependence, autism and Parkinson's disease.