Our exquisite sense of balance relies on a nervous system that senses and compensates for destabilizing forces. To understand these neural computations, we build and use cutting-edge tools to dissect, measure, probe, and model brain activity as fish develop balancing behaviors.
This data lets us discover fundamental principles of brain function, enabling us to understand, prevent, and treat disease.
To learn more about our mission, click the links in the statement above, or read on.
Why study fish?
One particular species, zebrafish, offers a unique set of advantages when trying to understand brain function. First, as larvae they are transparent, making it straightforward to leverage the latest advances in optical microscopy. Second, significant genetic groundwork makes molecular-level control and monitoring of brain activity straightforward. Third, their brains are much smaller. Taken together, fish are an ideal model system to uncover general principles of nervous system function.
Fish and humans use similar neural architecture and strategies to maintain postural stability. Consequentially, our work translates well to an understanding of normal human balance. Similarly, we aim to leverage the simplicity and molecular control of the fish model to understand and ultimately treat disease states.
Why study balance?
We propose that the computations necessary to balance are general in nature. By focusing on balance, we can understand the way our brains represent and utilize sensations to guide appropriate behavior.
The vestibular (or balance) system is a uniquely accessible model circuit to ask how the brain transforms sensation (forces on the body) to action (reflexive, corrective movements). Stabilizing posture and gaze are dynamic processes that can be reliably evoked by well-defined stimuli. Anatomically, we know the relevant neural projections from the sensory to motor periphery. The larval zebrafish permits molecular-level control at each stage, and the ability to monitor activity in many neurons simultaneously. We can therefore define the computations necessary for a sensorimotor transformation with rigorous control.
As scientists, much of what we do has never been done before, and requires new technology. In service of our science, we innovate in many domains, from genomic engineering to machining novel apparatus. Often, this innovation happens together with our collaborators, who bring a domain of expertise to the table. We could not be happier to discuss such collaborations; we’ve got a lot to learn.
We believe that the more we share the technologies we develop, the stronger the field. To that end, we’ve found it most effective to host people to come learn how we do what we do. Please contact us if you’re interested.
How do we dissect circuits?
One particular strength of the balance circuit is its comparatively constrained anatomy. Much of our work rests on a wiring diagram, elucidated over many years of work. The straightforward connectivity allows us to identify functional bottlenecks at the transition between stages.
Our main tool to dissect this circuit and measure the functional limits that arise at each junction is single-cell labeling. We have developed a set of protocols and reagents that allow us to molecularly target individual neurons at every stage of the circuit. This allows us unprecedented control over the balance circuit, at each node from sensation to action.
How do we measure brain activity?
We measure neural activity two ways: electrophysiologically, and optically. Together, they offer the ability to monitor the balance circuit with high spatial and temporal resolution. Electrophysiological measurements allow us to monitor the membrane potential of individual neurons at physiologically-relevant timescales. Optical recordings of genetically-encoded indicators complement these measurements, allowing us to characterize entire populations of neurons simultaneously.
How do we probe the balance circuit?
We interrogate the balance circuit in two ways: with natural stimuli, and with optically-gated ion channels. We read out the results of our perturbations both by monitoring behavior and its associated neural activity.
Larval zebrafish rapidly develop a set of sophisticated behaviors. Stable gaze and posture are vital to this repertoire, which includes meeting complex challenges like hunting and predator avoidance. Over the first few days of life, the nervous system rapidly wires the necessary balance circuitry. We aim to relate the molecular-level events necessary to establish the balance system to its fundamental functional limits. We believe that defining this relationship is crucial to understand disease.
Limits: how does the brain decode?
Sensory neurons in the balance circuit encode information about destabilizing forces. Downstream neurons use that information to correct gaze and posture. We’ve learned quite a bit about the limits of sensory neurons with respect to encoding, or representing, sensory information. In contrast, we know almost nothing about how downstream neurons interpret and process these signals. This "decoding" step places a fundamental limit on the brain's ability to transform sensation into action. It’s largely unexplored, and we’re going to understand it.
How does this research help us treat disease?
From a public health perspective, disorders of the vestibular, or “balance system,” are a big deal: recent estimates are that one of every three Americans over 40 have experienced a balance problem. While there are treatments for some of these disorders, many remain debilitating. Understanding normal function of the vestibular system is a necessary first step towards designing targeted therapies.