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.
References (Selected Publications)
- McPherson AD, Barrios JP, Luks-Morgan SJ, Manfredi JP, Bonkowsky JL, Douglass AD, Dorsky RI (2016) Motor Behavior Mediated by Continuously Generated Dopaminergic Neurons in the Zebrafish Hypothalamus Recovers after Cell Ablation. Current Biology 26:263-9
- Son JH, Keefe MD, Stevenson TJ, Barrios JP, Anjewierden S, Newton JB, Douglass AD, Bonkowsky JL (2016) Transgenic FingRs for Live Mapping of Synaptic Dynamics in Genetically-Defined Neurons. Scientific Reports 6:18734
- Duncan RN, Xie Y, McPherson AD, Taibi AV, Bonkowsky JL, Douglass AD, Dorsky RI (2016) Hypothalamic radial glia function as self-renewing neural progenitors in the absence of Wnt/β-catenin signaling. Development 143:45-53
- Safavi-Hemami H, Gajewiak J, Karanth S, Robinson SD, Ueberheide B, Douglass AD, Schlegel A, Imperial JS, Watkins M, Bandyopadhyay PK, Yandell M, Li Q, Purcell AW, Norton RS, Ellgaard L, Olivera BM (2015) Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc Natl Acad Sci U S A 112:1743-8
- Zou P, Zhao Y, Douglass AD, Hochbaum DR, Brinks D, Werley CA, Harrison DJ, Campbell RE, Cohen AE (2014) Bright and fast multicoloured voltage reporters via electrochromic FRET. Nature Communications 5:4625
- Kralj JM*, Douglass AD*, Hochbaum DR*, Cohen AE (2011) Optical recording of action potentials in mammalian neurons with a voltage indicating protein. Nature Methods 9:90-95
- Kralj JM, Hochbaum DR, Douglass AD, Cohen AE (2011). Electrical spiking in Escherichia coli probed with a fluorescent voltage-indicating protein. Science 333:345-348
- Douglass AD, Kraves S, Deisseroth K, Schier AF, Engert F (2008). Escape behavior elicited by single, channelrhodopsin-2-evoked spikes in zebrafish somatosensory neurons. Current Biology 18:1133-7
- Douglass AD*, Kaizuka Y*, Varma R, Dustin ML, Vale RD (2007). Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells. PNAS 104:20296-301
- Douglass AD and Vale RD (2005). Single molecule microscopy reveals plasma membrane microdomains created by protein-protein networks that exclude or trap signaling molecules in T cells. Cell 121:937-50