Dr. Wickersham and colleagues will develop nontoxic viral tracers to assist in the study of neural circuitry underlying complex behaviors.
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.
Public Health Relevance Statement
We will engineer and test novel systems for identifying synaptically connected networks of neurons within the brain and causing them to express introduced genes over much longer time periods than is possible with current technology. This 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. The result will be a greatly enhanced understanding of the neural circuitry underlying cognitive operations as well as neurological and mental disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, epilepsy, autism spectrum disorders, and many others.
NIH Spending Category
Behavioral and Social Science; Bioengineering; Brain Disorders; Eye Disease and Disorders of Vision; Genetics; Mental Health; Neurosciences
Acute; Address; Alzheimer’s Disease; Animals; Area; autism spectrum disorder; base; Behavior; Behavioral; Behavioral Paradigm; Brain; calcium indicator; Cognition; Cognitive; Complex; Engineering; env Gene Products; Epilepsy; Flow Cytometry; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; genetic technology; Huntington Disease; Image; In Situ; in vivo; Individual; Infection; Killings; Label; Left; Lentivirus Vector; Mental disorders; Modeling; Monitor; Mus; mutant; nervous system disorder; neural circuit; Neurons; Neurosciences; new technology; novel; operation; optic imaging; optogenetics; Parkinson Disease; particle; Physiological; Population; Presynaptic Terminals; Primates; Problem Solving; public health relevance; Rabies; Rabies virus; Rattus; recombinase; relating to nervous system; Reporter; Research Personnel; research study; Resolution; Rodent; Role; Slice; Synapses; System; Techniques; Technology; Testing; Time; tool; Toxic effect; transgene expression; Transgenes; Transgenic Organisms; vector; Viral; Viral Genes; Viral Genome; Viral Vector; Virus; virus envelope; Whole-Cell Recordings