Our research is directed at understanding electrical signaling in the brain. Information in the brain is encoded as patterns of "action potentials", brief (~ 1 millsecond) reversals of the voltage across the membrane of neurons. Different neurons in the brain fire action potentials with a wide variety of distinct patterns. We seek to understand the different patterns of firing in terms of the underlying molecular devices - tiny pores in the membrane known as ion channels. In mammalian brains, each neuron possesses several dozen different types of ion channels. Most of these are closed when the neuron is at rest (electrically silent), and it is the coordinated, transient opening ("gating") of particular types of ion channels that underlies electrical signaling.
To understand how different combinations of ion channels work together to generate the distinct patterns of action potential firing in different neurons, we make electrical recordings from individual neurons using the patch clamp technique, either from neurons in brain slice preparations or from isolated neurons prepared using mild enzymatic treatment and mechanical dissociation. Gating of particular types of ion channels can be characterized at a sub-millisecond timescale using voltage clamp recordings, with components of electrical current carried by different types of ion channels separated using selective drugs or changes in the ionic composition of extracellular or intracellular solutions.
Current projects are focused on understanding the mechanism by which some neurons can generate spontaneous electrical activity ("pacemaking"). These include studies on dopamine-secreting neurons in the midbrain that are part of the reward system and studies of particular classes of GABA-secreting neurons in the cerebral cortex and the cerebellum that are unusual for their ability to generate ultra-rapid electrical signaling.
We are also interested in the pharmacology of ion channels. Many clinically-used pharmacological agents, including antiepileptic drugs, interact with voltage-dependent channels. We are exploring how antiepileptic drugs can prevent abnormal firing patterns in cortical circuits without disrupting normal firing, with the goal of improving antiepileptic activity while minimizing side effects. In collaboration with Clifford Woolf at the Massachusetts General Hospital, we are also developing novel treatments for pain based on introducing charged derivatives of local anesthetics like lidocaine through the pore of TRPV1 channels, which are selectively expressed on pain-sensing neurons. This allows long-lasting inhibition of pain sensing fibers with no effect on motor fibers or sympathetic fibers and should be an improved method of local anesthesia.
Flow of current through sodium-selective (red) and calcium-selective (blue) ion channels in between (left) and during (right) spontaneous action potentials formed by dopamine-secreting cells in the substantia nigra pars compacta. Electrical current carried by calcium ions generates the spontaneous activity, and massive amounts of calcium also enter during the action potential. The calcium entry may help make the neurons susceptible to cell death in Parkinson's disease.