We are interested in the role of nicotinic cholinergic signaling both in guiding the formation of complex neural networks and in regulating their function. We find that endogenous nicotinic activity promotes early glutamatergic (excitatory) innervation of neurons during development. Further, it helps drive the conversion of GABAergic transmission from excitation to inhibition at this time. Direct exposure to nicotine during early development produces long-lasting changes in synaptic wiring that persist into the adult and remain long after nicotine cessation. These kinds of changes suggest serious behavioral consequences and increased vulnerability to subsequent nicotine challenges. We are also pursuing other mechanisms guiding network formation, including the role of micro-RNAs in orchestrating major transitions in brain development.
Our laboratory takes a multidisciplinary approach. We want to identify the molecular players mediating nicotinic signaling and understand how they work. We want to understand how these components interact in complex ways to regulate circuit construction and system output. To do this, we combine molecular, physiological, imaging, and biochemical techniques, applying them both in acute slices and in vivo. Recent collaborations have also incorporated computational and ultrastructural analyses. We use viral constructs and mutant mice to manipulate signaling pathways in vivo both during development and in the adult to gain insight into mechanism.
It is an exciting time to be investigating nicotinic signaling in the central nervous system. At the behavioral level nicotinic cholinergic activity has been implicated in a broad array of phenomena including cognition, memory formation, and arousal. It is also associated with numerous pathologies including Alzheimer's disease, schizophrenia, and addiction. These physiological consequences of nicotinic activity offer intriguing windows into higher brain function while at the same time suggesting biomedical applications. How the cellular and molecular features of nicotinic signaling collaborate to achieve these effects in the brain remains a mystery and presents ongoing challenges. Molecular tools are now in place to make major advances in these areas.