Projects

Research Interests: Neural Plasticity Related to Pain
Nociception (the perception of pain) is a critical function of the nervous system that protects us from additional injury or death. My lab is interested in the cellular mechanisms of how nociception is modulated focusing on a class of lipid neurotransmitters referred to as endocannabinoids. Specifically, we are examining how endocannabinoids can have both anti-nociceptive and pro-nociceptive effects. Our research suggests that these transmitters differentially modulated nociceptive and non-nociceptive synapses, depressing nociceptive synapses (an anti-nociceptive effect) and potentiating non-nociceptive synapses (a potentially pro-nociceptive effect).

These studies utilize the medicinal leech, Hirudo verbana, as a model system because the nervous system in Hirudo is very well characterized in terms of the identity, functional role and synaptic connections of individual neurons. This makes it possible to carry out detailed analyses of pre– versus postsynaptic cellular mechanisms mediating synaptic plasticity and to link plasticity in individual neurons or synapses to changes at the behavioral level. The lab utilizes electrophysiological, behavioral, and molecular biology approaches to address these questions about endocannabinoids and nociception. This comparative approach can uncover fundamental mechanisms of nociception and endocannabinoid modulation that may also have applications for the treatment of chronic pain. 

Neuroplasticity related to nociception and injury-induced sensitization

We have been examining the ability of endocannabinoids, e.g., 2-arachydonoylglycerol (2-AG), to having opposing effects on nociceptive vs. non-nociceptive synapses. 2-AG, through activation of TRPV channels, elicits LTD of nociceptive synapses, but potentiates/disinhibits non-nociceptive synapses. Part of what regulates these opposing effects of endocannabinoids are differences in Cl gradients between the two afferents.

 

We are also developing behavioral experiments in which to study nociception.  These include reduced preparations in which it is possible to monitor both behavior and electrophysiological properties of individual neurons.  We are also carrying out in vivo experiments in which we look at habituation and sensitization in Hirudo, the effects of endovanilloids on responses to nociceptive and non-nociceptive stimuli, and the role that endovanilloid signaling may play in stress-induced modulation of nociception.  The goal of these experiments will be assess the ability of endocannabinoids to ameliorate injury-induced sensitization. 

These projects involve a combination of behavioral, electrophysiological and molecular biological approaches.  We have recently cloned the 2-AG synthesizing and metabolizing enzymes and are beginning to examine how they are regulated and where they are located in the nervous system.

 

Serotonergic modulation of excitability and electrical synapses

Serotonin is an important neuromodulatory transmitter that is critical for both associative and non-associative forms of learning in the leech.  During sensitization of the shortening reflex, serotonin increases excitability of the S-cell, an interneuron known to be critical for this form of learning in the leech.  This increase in excitability is due, at least in part to modulation of S-cell afterhyperpolarization (AHP).  We are currently studying what ion channels mediate the S-cell AHP and how they are modulated by serotonin.  This project is carried out in collaboration with Prof. Kevin Crisp at St. Olaf College (http://www.stolaf.edu/depts/biology/faculty/dr_kevin_crisp/index.html) who utilizes computational modeling techniques to address questions that cannot be answered with electrophysiological techniques.

 

In addition to modulating excitability, serotonin also modulates the electrical synapses that link the S interneurons to one another, altering the manner in which information is transmitted through this interneuron network.  Part of this work has involved developing a computational model of the S-cell network, which can be accessed at http://senselab.med.yale.edu/SenseLab/ModelDB/ShowModel.asp?model=53559.
 

Recording setup for leech ganglion

 
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