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

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01MH106018-01
Application #
8822590
Study Section
Special Emphasis Panel ()
Program Officer
Freund, Michelle
Project Start
2014-09-26
Project End
2017-06-30
Budget Start
2014-09-26
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$699,916
Indirect Cost
$251,252
Name
Massachusetts Institute of Technology
Department
None
Type
Organized Research Units
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142