About

Theodore Lindsay, PhD

Postdoctoral Scholar
Dickinson Lab, Caltech
thlindsay1 at gmail dot com
1200 E. California Blvd
Pasadena, Ca 91125

Research interests

I am a postoctoral scholar working in the Dickinson Lab at the California Institute of Technology. I am broadly interested in how a nervous system endows an animal with agency in the world around it. To generate behavior, an animal's nervous system must respond to incoming sensory information and respond with the appropriate motor acts. This is a challenging problem since it requires neural networks that can decode a constant stream of information arriving from an array of diverse sensors; transform this information into motor commands that will produce a desired response; and do this within the constraints placed by the physics of the body. Moreover, this operation must be updated in real time, since the movement itself will change what the animal senses. Finally, the operation should account for the internal desires and intention of the animal: is it searching for food? courting a mate? defending a resource? recovering from illness of injury? I view behavior as the result of a continuous loop in which reaction is fused with intention, transformed into action that updates sensation.

I have studied the neural elements of this loop at several levels, in several different model systems. Following my undergraduate degree, I investigated how sensory neurons of mice responded to the injury of bone and pancreatic cancer. For my doctoral work, I studied how the simple neural network of the nematode C. elegans might process noxious stimuli while the worm searches for food.

Now, I am looking at a small set of motor neurons that the frutfly uses to steer in flight. Recently, I developed a technique that allows us to optically record the activity of this motor network in intact flies as they fly in a virtual reality flight simulator. My hope is this approach will provide a window into the inner workings of the sensorimotor loop used to execute nimble areal maneuvers.

Publications

Motor control of flight in flies

Lindsay T.H., Sustar A., Dickinson M.H., The function and organization of the motor system controlling flight in flies. Current Biology. 2017, 345-348.

This is the video abstract that accompanies the above paper. It is a short ~5 min description of the major findings.

Biophysics of search and avoidance in nematodes

Ardiel E.L., Giles A.C., Alex J.Y., Lindsay T.H., Lockery S.R., Rankin C.H. Dopamine receptor DOP-4 modulates habituation to repetitive photoactivation of a C. elegans polymodal nociceptor. Learning & Memory. 2016 Oct 1;23(10):495-503.

Kato S, Kaplan H.S., Schrödel T, Skora S, Lindsay TH, Yemini E, Lockery S, Zimmer M. Global brain dynamics embed the motor command sequence of Caenorhabditis elegans. Cell. 2015 Oct 22;163(3):656-69.

Roberts, W.M., Augustine, S.B., Lawton, K.J., Lindsay, T.H., Thiele, T.R., Izquierdo, E.J., Faumont S., Lindsay, R.A., Britton, M.C., Pokala, N.,Bargmann, C.I., Lockery, S.R., A stochastic neuronal model predicts random search behaviors at multiple spatial scales in C. elegans. eLife. 2016 Jan 29;5:e12572.

Faumont, S., Lindsay, T. & Lockery, S. Neuronal microcircuits for decision making in C. elegans. Current Opinion in Neurobiology (2012).doi:10.1016/j.conb.2012.05.005

Lockery S.R., Hulme S.E., Roberts W.M., Robinson K.J., Laromaine A, Lindsay T.H., Whitesides G.M., Weeks J.C. A microfluidic device for whole-animal drug screening using electrophysiological measures in the nematode C. elegans. Lab Chip 12, 2211–2220 (2012).

Goodman, M. B., Lindsay, T., Lockery, S. R. & Richmond, J. E. Electrophysiological methods for Caenorhabditis elegans neurobiology. Methods Cell Biol. 107, 409–436 (2012).

Lindsay, T., Thiele, T. R. & Lockery, S. R. Optogenetic analysis of synaptic transmission in the central nervous system of the nematode Caenorhabditis elegans. Nat Commun 2, 306–9 (2011).

This shows the procedure I used to record synaptic currents from the locomotor command neurons of the nematode worm C. elegans. The video shows a recording from the AVA-neuron class which is involved in generating backward locomotion. The entire worm is about 1mm long, but the view in the video is focused on an area near the head where an important ganglion (collection of neurons) is located. In order to perform the procedure, the worms must first be fixed in place to a gelatinous film with some veterinary adhesive, and then immersed in a saline solution. Since these nematodes have a pressurized hydroskeleton we access the cells by making a very small puncture in the cuticle with a sharpened glass needle. If we're lucky, the internal pressure of the worm will push the neurons of interest out of the cuticle, exposing them to our recording electrode. We use transgenic worms that have been engineered to express a fluorescent protein in the target cells so we can visualize them under the microscope. To record the electrical potential inside the neuron we make use of the whole cell technique: we use a glass electrode, (a thin glass tube that has been carefully shaped with heat and pressure, like a venetian might shape fine stemware) and form a tight seal between the neuron and the tip of the electrode. After forming this seal, a small bleb of the cell membrane appears inside the electrode. With a little suction we break this bleb and the saline inside the electrode becomes electrically contiguous with the voltage inside the neuron

Neurochemistry of cancer pain in mice

Sevcik M.A., Jonas B.M., Lindsay T.H.*, Halvorson K.G., Ghilardi J.R., Kuskowski M.A., Mukherjee P., Maggio J.E., Mantyh P.W. Endogenous opioids inhibit early-stage pancreatic pain in a mouse model of pancreatic cancer. Gastroenterology 131, 900–910 (2006).

Lindsay T.H., Jonas B.M., Sevcik M.A., Kubota K., Halvorson K.G., Ghilardi J.R., Kuskowski M.A., Stelow E.B., Mukherjee P., Gendler S., Wong GY., Mantyh P.W. A quantitative analysis of the sensory and sympathetic innervation of the mouse pancreas. Neuroscience 137, 1417–1426 (2006).

Lindsay T.H., Jonas B.M., Sevcik M.A., Kubota K., Halvorson K.G., Ghilardi J.R., Kuskowski M.A., Stelow E.B., Mukherjee P., Gendler S., Wong GY., Mantyh P.W. Pancreatic cancer pain and its correlation with changes in tumor vasculature, macrophage infiltration, neuronal innervation, body weight and disease progression. Pain 119, 233–246 (2005).

Sevcik M.A., Ghilardi J.R., Peters C.M., Lindsay T.H., Halvorson K.G., Jonas B.M., Kubota K., Kuskowski M.A., Boustany L., Shelton D.L., Mantyh P.W. Analgesic efficacy of bradykinin B1 antagonists in a murine bone cancer pain model. J Pain 6, 771–775 (2005).

Halvorson K.G., Kubota K., Sevcik M.A., Lindsay T.H., Sotillo J.E., Ghilardi J.R., Rosol T.J., Boustany L., Shelton D.L., Mantyh P.W. A blocking antibody to nerve growth factor attenuates skeletal pain induced by prostate tumor cells growing in bone. Cancer Res. 65, 9426–9435 (2005).

Sevcik M.A., Ghilardi J.R., Peters C.M., Lindsay T.H., Halvorson K.G., Jonas B.M., Kubota K., Kuskowski M.A., Boustany L., Shelton D.L., Mantyh P.W. Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization. Pain 115, 128–141 (2005).

Ghilardi J.R., Rorhrich H., Lindsay T.H., Sevcik M.A., Schwei M.J., Kubota K., Halvorson K.G., Poblete J., Chaplan S.R., Dubin A.E., Carruthers N.I., Swanson D., Kuskowski M., Flores C.M., Julius D., Mantyh P,W. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain. J. Neurosci. 25, 3126–3131 (2005).

Peters, C.M., Ghilardi, J.R., Keyser, C.P., Kubota, K., Lindsay, T.H., Luger, N.M., Mach, D.B., Schwei, M.J., Sevcik, M.A., Mantyh, P.W. Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain. Exp. Neurol. 193, 85–100 (2005).

Peters, C.M., Lindsay, T.H., Pomonis, J.D., Luger, N.M., Ghilardi, J.R., Sevcik, M.A., Manyh, P.W. Endothelin and the tumorigenic component of bone cancer pain. Neuroscience 126, 1043–1052 (2004).

This image shows co-expression of the activating transcription factor ATF-3 and the capsacian receptor TRPV1.