Smoking-related diseases result in more than 400,000 premature deaths in the United States each year1, yet thousands struggle with smoking cessation. Nicotine, the major addictive component in tobacco, interacts with specific classes of nicotinic acetylcholine receptors (nAChRs), altering the functional state of the receptors and expression at the cell surface. Although the role of nAChRs in nicotine addiction has been well established, mechanisms for the biological regulation of these receptors during normal brain function and following nicotine exposure are poorly defined. In this proposal, I will use the model system C. elegans to investigate the dynamics of nAChRs on the neuronal cell surface. [In Aim 1, I will define the subunit composition of nAChRs expressed on the dendrites of GABAergic motor neurons. Secondly, I will investigate the role of OIG-1, an immunoglobulin domain protein, in nicotinic receptor clustering.] Finally, in the third Aim I will investigate how neuronal activity and nicotine exposure shape the dynamics and subcellular distribution of nAChRs. These studies will address fundamental questions about the biology of nAChRs and provide me with strong training in genetics, microscopy, and electrophysiology techniques that will be essential tools in my continuing scientific development.
The regulation of nicotinic acetylcholine receptors (nAChRs) has been implicated in a variety of neurological diseases, including Alzheimer's disease and nicotine addiction. The proposed work will address fundamental questions about the in vivo biology of neuronal nAChRs using the model system Caenorhabditis elegans. Ultimately, understanding receptor function will help shape the treatment and prevention of diseases with nicotinic receptor abnormalities.
| Philbrook, Alison; Ramachandran, Shankar; Lambert, Christopher M et al. (2018) Neurexin directs partner-specific synaptic connectivity in C. elegans. Elife 7: |
| Barbagallo, Belinda; Philbrook, Alison; Touroutine, Denis et al. (2017) Excitatory neurons sculpt GABAergic neuronal connectivity in the C. elegans motor circuit. Development 144:1807-1819 |
| He, Siwei; Philbrook, Alison; McWhirter, Rebecca et al. (2015) Transcriptional Control of Synaptic Remodeling through Regulated Expression of an Immunoglobulin Superfamily Protein. Curr Biol 25:2541-8 |
