Timothy Holy, PhD

Timothy Holy, PhD

Alan A. and Edith L. Wolff Professor, WashU Neuroscience

Neural mechanisms of pheromone detection, recognition, and olfactory learning; novel optical methods for recording neuronal activity

In my laboratory, we focus on two major areas of research: (1) studying the neural mechanisms of detecting and recognizing pheromones, and (2) developing new optical methods for imaging neuronal activity.

In the mouse, pheromones are detected primarily by the neurons of the vomeronasal organ, which project their axons to a distinct brain region called the accessory olfactory bulb. This system is of interest to us because of the close coupling between sensory input and behavioral output—evidence suggests that only a few layers of synaptic processing are needed to recognize specific stimuli and even to form long-lasting memories of them.

We have made a number of foundational discoveries in this system. At the level of the sensory receptors, we recently found that the large majority of the neuronal activity triggered by a natural stimulus—female mouse urine—is due to sulfated compounds, particularly sulfated steroids. This observation implies that a primary purpose of this sensory system is to detect information about physiological state. This discovery follows on our older work elucidating the core elements of the signal transduction cascade for converting chemical information into electrical activity.

At the circuit level, we have provided the first recordings from downstream neurons in a well-controlled preparation, and have discovered significant roles for inhibition in reshaping stimulus representations and directing behavior.

Future work in this system will explore the nature of sensory coding at all stages of this pathway, identify new molecules detected by these neurons, and explore the molecular and circuit underpinnings of pheromone-driven behaviors. One such behavior that we recently discovered is the fact that pheromones trigger male mice to sing.

On a technical level, we have developed a new method for imaging neuronal activity simultaneously in large neuronal populations. This approach, called objective-couple planar illumination microscopy, uses a sheet of light to provide three-dimensional resolution without point-scanning. The principal advantage of this technique is that hundreds or thousands of neurons can be imaged high speed and high signal-to-noise ratio. Current work on this technology includes optical and algorithmic methods for enhancing resolution deeper into tissue.

More about the Holy lab