Novel technologies for nontoxic transsynaptic tracing

Massachusetts Institute Of Technology, Cambridge MA

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Abstract

? DESCRIPTION (provided by applicant): Genetic tools have dramatically increased the power and resolution of neuroscientific experiments, allowing monitoring and perturbation of specific neuronal populations within the brain, often in the context of complex cognitive and behavioral paradigms. However, the usefulness of these tools is limited by the available means of delivering them in circuit-specific ways, a major drawback in view of the critical importance of specific connectivity between individual neurons and between neuronal classes. The primary available means of achieving transgene expression based on neurons' synaptic connections is virus-based transsynaptic tracing, which allows identification, activity imaging, optogenetic control, and perturbation of gene expression in networks of synaptically connected neurons in vivo. The required viruses, however, are toxic within a few days, precluding longer-term experiments that are needed to address many central questions in neuroscience. We will solve this problem by engineering viral transsynaptic tracing systems with either greatly reduced or entirely eliminated toxicity, so that the role of neuronal networks of known connectivity in cognition and behavior. The result will be a set of tools that will allow optical imaging, physiological recording, and manipulation of the activity and gene expression of neuronal networks of known synaptic connectivity in the context of behavioral and other experimental paradigms lasting weeks, months, or years, in any mammalian model species. This will greatly enhance our understanding of the neural bases of normal cognition as well as neurological and mental disorders.