Assistant Professor of Neurobiology and Anatomy
Functional anatomy of neuromodulatory circuits; learning and memory in the larval zebrafish; imaging technique development
The modulatory neurotransmitters dopamine and serotonin play crucial roles in locomotion, learning, reward encoding, and a variety of other brain functions. We know very little about what allows the relatively small populations of neuromodulatory cells to fill such diverse behavioral roles. How is it that release of dopamine from midbrain nuclei affects an animal's ability to move in one context, and causes feelings of pleasure in another? The answer certainly involves functional heterogeneity among modulatory cells, but it has been difficult to isolate the contributions of single neurons. We are interested in how differences in connectivity and activity among these neurons - at the level of single cells within an intact brain - dictate their behavioral roles.
To account for the varied effects of dopamine and serotonin on neuronal activity and behavior, we need a way to manipulate and record single-cell activity within ensembles of neurons. New imaging and optogenetic methodologies have dramatically improved our ability to do this. As an optically transparent vertebrate with a complex behavioral repertoire, the larval zebrafish provides a powerful model system in which to use these techniques. My lab has three, primary goals:
(1) Characterize the physiological interactions of individual dopaminergic and serotonergic neurons with the entire zebrafish brain. We are using a combination of molecular biology, channelrhodopsin-based photoactivation, and functional imaging techniques to determine how these cells influence neuronal activity. By comprehensively mapping such interactions, we will define the circuits that constrain neuromodulator activity.
(2) Create and extend new optical methods for studying neuronal function. During my postdoc, I helped develop a novel, voltage-imaging technique that allows one to visualize single action potentials in cultured neurons. We are now applying this approach to intact animals, and devising ways to combine it with optogenetics to better understand how neurons - including modulatory ones - talk to one another.
(3) Develop new paradigms to study learning and behavior in the larval zebrafish. Adult zebrafish are surprisingly smart, and very capable of learning. Recent efforts have hinted at similar capabilities in larval animals. We will devise new ways of looking at reward learning, locomotion, and other modulator-driven behaviors at these earlier developmental stages, when the brain can be studied in its entirety.
Kralj, J.M.*, Douglass, A.D.*, Hochbaum, D.R.*, and Cohen, A.E. (2011) Optical recording of action potentials in mammalian neurons with a voltage indicating protein. Nat Methods, 9:90-95. *Equal contribution
Kralj, J.M., Hochbaum, D.R., Douglass, A.D., and Cohen, A.E. (2011) Electrical spiking in Escherichia coli probed with a fluorescent voltage-indicating protein. Science, 333:345-348.
Douglass, A.D., Kraves, S., Deisseroth, K., Schier, A.F., and Engert, F. (2008) Escape behavior elicited by single, channelrhodopsin-2-evoked spikes in zebrafish somatosensory neurons. Curr Biol, 18:1133-1137.
Douglass, A.D.*, Kaizuka, Y.*, Varma, R., Dustin, M.L., and Vale, R.D. (2007) Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells. PNAS, 104:20296-20301. *Equal contribution
Douglass, A.D., and Vale, R.D. (2005) Single molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell, 121:937-950.