What is the scientific problem that the nominee will address, and why is this important?What are the pioneering, and possibly high-risk, approaches that, if successful, might lead togroundbreaking results?Understanding brain function is a major outstanding question in biomedical science. Recentlyit has become clear that a major bottleneck in our progress in understanding of brain function is agap, or rather an abyss, in our knowledge of the wiring diagram of the brain. This is a problem offundamental importance because many neurological diseases arise from anomalies of thedevelopment of brain circuitry. Recent studies in schizophrenia, depression, bipolar disease,learning disabilities, autism, and X-linked mental retardations all point to developmental etiologiesrelating to aberrant circuit connections. Nevertheless, the normal connectivity of the brain is still amystery and importantly, the methods for determining neuronal connectivity are severely limited.Failure to establish the requisite synaptic connectivity in brain circuits, or failure to refinetopographic sensory or motor maps in response to experience, has devastating effects on circuitfunction. Nevertheless, how these brain circuits develop and change with experience has beendifficult to ascertain due to limited methodologies. It is even more of a mystery how changes in thedevelopment of neuronal circuits can affect particular aspects of cognitive function andneurological health. A first step toward addressing these questions is to develop new technologiesto determine neuronal connectivity in living animals.Over the next 5 years a major effort in my lab will be to develop a method to determine brainconnectivity in vivo and to apply this method to address several fundamental questions pertainingto circuit formation and plasticity within the visual system. To know the underlying architecture ofthe brain, we must solve the who is connected to whom question. Because of its overarchingimportance, many labs are addressing this question. One recent approach has been to use serialsection electron micrographs to identify and reconstruct neural networks. This method provideshigh resolution analysis, but it is labor intensive and only applicable to fixed tissue. Manyinvestigators have concentrated on identifying reagents to cross synapses, such as wheat germagglutinin [1], however one problem with this approach is that there is not a reliable way toamplify the signal in the downstream neurons. Without amplification, identification of downstreamneurons poses a significant detection problem. Although some viruses may allow for amplification,I propose a different strategy based on the use of Trojan peptides and amplification through amodification of the Gal4/UAS system.
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