Neural circuits and behavior
Our laboratory is interested in elucidating the circuitry that drives behavior normally and in disease. We are currently focused on the somatosensory system, which detects touch, temperature and pain and on forebrain cholinergic circuits, which are important for mood, cognition and the execution of motor behavior.
Somatosensory System: Understanding the neural basis of touch and pain.
One major effort of our laboratory is to study neural circuits underlying touch and pain. In a recent study, we found that the vesicular glutamate transporter 3 is required for the chronic mechanical pain that results from nerve injury and inflammation. This form of pain manifests as a hypersensitivity to touch or movement and is distinct from thermal pain. Although it is the most clinically relevant form, the mechanisms that generate and maintain it are still not well-understood nor are there efficacious, non-addictive treatment options. The laboratory is actively trying to understand precisely how VGLUT3 contributes to this form of pain and in doing so, will identify circuits, synapses and molecules essential for the transmission of chronic pain. We intend to use this knowledge to generate novel, non-addictive therapies.
Forebrain Cholinergic Circuits: The role of glutamatergic-cholinergic co-release in cognition and motor function.
A second major effort of the laboratory is to determine the behavioral role of vesicular glutamate packaging and release by forebrain cholinergic neurons. These cells were only recently shown to use glutamate as a neurotransmitter and we are now testing what role this signaling has in behavior. In addition, glutamate transport into cholinergic vesicles can increase vesicular acetylcholine content. Thus co-packaging of the two transmitters can also have an impact on neurotransmission and behavior. Dysfunction of forebrain cholinergic neurons contributes to several neuropsychiatric disorders such as Parkinson’s disease, schizophrenia and Alzheimer’s disease and cholinomimetics are often used as treatments. Work in our laboratory suggests that vesicular glutamate packaging and release by the cells influences cognitive and motor behavior and could provide new therapeutic strategies for these disorders.
The laboratory uses mice as a model system and techniques such as virus-mediated circuit tracing, confocal and 2-photon microscopy, molecular biology, slice electrophysiology with optogenetics and behavior.
We are currently seeking highly motivated graduate students and postdocs who are interested in these systems to join our group.
Akil, O., Seal, R.P., Burke, K., Wang, C., Alem, A., During, M.J., Edwards, R.H. and Lustig, L.R. Restoration of Hearing in the VGLUT3 Knockout Mouse Using Virally-Mediated Gene Therapy. Neuron 2012 (in press)
Seal, R.P., Wang, X., Guan, Y., Raja, S.N., Woodbury, C.J., Basbaum, A.I. and Edwards, R.H. Injury-induced mechanical hypersensitivity requires C-low threshold mechanoreceptors. Nature, Dec 3;462(7273): 651-5, 2009
Seal, R.P., Akil, O., Yi, E., Weber, C.M., Grant, L., Yoo, J., Clause, A., Kandler, K., Noebels, J.L., Glowatzki, E., Lustig, L.R. and Edwards, R.H. Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron. 2008 Jan 24;57(2):263-75
Seal, R.P. and Edwards, R.H. The diverse roles of vesicular glutamate transporter 3. Handb Exp Pharmacol. 2006 (175):137-50. Review.
Seal, R,P. and Edwards, R,H. Functional implications of neurotransmitter co-release: glutamate and GABA share the load. Curr Opin Pharmacol. 2006 6(1):114-9. Review.