Systems Neurobiology Laboratories
Audrey Geisel Chair in Biomedical Science
Edward M. Callaway is a professor in the Systems Neurobiology Laboratories. Work in his laboratory is aimed at understanding how neural circuits give rise to perception and behavior. Studies focus primarily on the organization and function of neural circuits in the visual cortex. Relating neural circuits to function in the visual system, where correlations between neural activity and perception can be directly tested, provides fundamental insight into the basic mechanisms by which cortical circuits mediate perception.
Neuroscientists have identified dozens of types of neurons in the brain that work together in distinct networks. But the circuits are intermingled, and even neighboring neurons of the same type differ in connectivity and function. Without access to a "wiring diagram"—a map of the neuronal connections— attempting to grasp how the brain lets us understand language, recognize faces and schedule our day is akin to trying to discern how a computer works simply by looking at it.
Recently, Callaway and his team have jumped a major hurdle to preparing that diagram: mapping single connections between neurons. They successfully modified the rabies virus so that it crosses from an infected nerve cell to another neuron just once, allowing scientists to identify all the neurons to which the infected neuron connects. Viruses that naturally spread between neurons have previously been used to trace the flow of nerve cell communication, but without a way to stop them in their tracks, over time, they will light up the whole brain.
Callaway's team deleted a gene required by the virus to spread between neurons, marooning the virus inside a cell. Supplying the missing gene in that same cell, however, allowed the virus to slip into all the cells that were directly connected to it but to spread no further. To restrict the viral infection to a certain cell type or even to single cells, they covered these neurons with avian surface molecules and equipped the rabies virus with a homing device specifically for neurons "disguised" as bird cells.
While the first experiments were conducted using slices of brain, more recent studies are using genetically modified mice to target a specific class of neurons. With these tools, the wiring map can then be constructed step by step as subsequent populations of cells are visualized. Callaway's lab then takes advantage of this information about each cell type's connections to match it with the functional visual responses of the same types of neurons under different conditions. This leads to ideas about how each cell type contributes to brain function that can be tested by selectively activating or inactivating cell types and observing the consequences.