Physicists may regard time's puzzle on a cosmic scale, but for neuroscientist Josh Dudman, the problem funnels down to a much smaller dimension: that of individual brain cells.

"The timing of the world does not always match the timing of the nervous system," says Dudman, who is curious about how the brain bridges the chasm between vastly different magnitudes of time.

The timing and sequence of the electrical signals in the brain shape an organism's decisions to carry out specific actions, particularly as it repeats and learns new behaviors. Each individual nerve impulse itself can be broken down into a sequence of events: stimulus, delay, and response. Delays imposed by the environment, Dudman says, "can be very long in terms of the timescale of the nervous system." In nervous-system time, he explains, a few hundred milliseconds is an eon.

The brain must constantly bridge these lengthy delays to seamlessly integrate complex actions. The fluid sequence of a tennis serve, for example, requires the brain to coordinate many smaller actions: tossing the ball, bringing the racket back, pausing for the ball to reach the top of its arc. When this timing goes awry, as in some compulsive disorders, the brain gets confused and responds to multiple stimuli with the same action.

At Janelia Farm, Dudman explores the timing of brain activity, especially in neural connections between regions of the brain known as the cerebral cortex and the basal ganglia. Dudman focuses his research on the striatum, the basal ganglia's main input station, which appears to play an important role in connecting and adjusting actions. Dudman wants to understand how the striatum translates a specific stimulus among the flood of incoming signals into the appropriate action.

"The temporal separation between stimulus and response is part of what makes this a really hard problem to solve," he says. Research has established that dopamine is critical in linking particular actions with a reward; Dudman wants to understand how dopamine helps reinforce particular behaviors by modulating individual neurons in response to sensory input.

"I've always been fascinated by a basic question," he says: "Why is each cell in the brain so complicated?" The answer appears to involve the need to adapt continuously. At Janelia, Dudman studies circuits in the striatum that are important for choosing an action. The complex cells in the striatal circuit are key to integrating and responding to the stream of sensory inputs.

To tease out the details of this complicated neural processing, Dudman focuses on a well-defined circuit: the one that controls the whisking action mice use to explore their surroundings—determining, for instance, whether their body will fit through a small crevice. By studying how mice learn to control this whisking action, Dudman hopes to better understand striatal neurons and their role in behavior. "These findings will start to elucidate how one neural circuit solves the problem of selecting and timing action performance," he says.

Dudman joins teams already working at Janelia Farm, including that of Karel Svoboda, who helped pioneer the use of two-photon imaging to see deep inside brain tissue. Dudman expects that combining his facility with tools for viewing brain activity with the expertise of other Janelia Farm scientists will yield uniquely powerful molecular tools. "I think it's a great place to be," he says.

Dudman says that the scientific questions at the center of his work can seem removed from human health—but the kind of study he intends to pursue at Janelia Farm could have clear clinical relevance. The question of how the brain chooses an action may have important implications for disorders such as Parkinson's disease and some forms of addiction. At Janelia, his intellectual interest—how cells determine brain function—dovetails with his desire for societal impact, a drive that stems from his summers working at the Movement Disorders Clinic at the University of Rochester as an undergraduate.

"I've always wanted to get back to that," he says. "My hope is that this work at Janelia is where my intellectual interests come together with my social interests." It could be a case of perfect timing.

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RESEARCH ABSTRACT SUMMARY:

Joshua Dudman is interested in understanding how the brain associates sensory input and motor output during the selection and performance of reinforced actions. His lab uses electrophysiological, imaging, and computational techniques to explore sensorimotor integration in the striatum both in vitro and in awake, behaving rodents. His long-term goal is to link computations in these circuits to the acquisition of reinforced behaviors.

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Photo: Courtesy of Matthew Septimus