One of the great challenges in neuroscience is to understand how the neurons of the brain work together as a circuit to compute behaviors, and how such circuit functions are changed in brain disorder states. There is a great need for technologies that enable the neural activity of large numbers of individual cells to be measured in the brain of a mammal such as a mouse - ideally throughout the entire brain, since we do not precisely know the exact set of cells involved with any behavior or brain disorder. We here propose two radical departures from the past, using computational and theoretical analyses to design new neural recording devices, and augmenting these technologies with supplementary tools to enable the bridging of dynamic and anatomical pictures of the brain. As we validate these technologies, we will examine whole-brain neural dynamics and anatomical phenotypes in autism and schizophrenia mouse models, performing whole-brain activity mapping to characterize the altered computations associated with psychiatric illness. Such maps may fundamentally open up new frontiers in thinking about how distributed brain circuits are changed in mental illness, paving the way to new treatment strategies.

Public Health Relevance

The brain is a three-dimensional, densely wired circuit made of cells which interact at a fast timescale. I propose to develop a set of technologies that enable an analysis of how neurons distributed throughout the entire brain compute to implement behavior, and how these interactions go awry in brain disorders. This ability to map such widespread neural dynamics will yield new and fundamental principles of how neural circuits compute, and these technologies will also enable scientists and clinicians to develop new, efficacious, side-effect free treatments to confront the spectrum of neurological and psychiatric disorders.

Agency
National Institute of Health (NIH)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1NS087724-02
Application #
8738739
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ludwig, Kip A
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Miscellaneous
Type
Other Specialized Schools
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Tillberg, Paul W; Chen, Fei; Piatkevich, Kiryl D et al. (2016) Protein-retention expansion microscopy of cells and tissues labeled using standard fluorescent proteins and antibodies. Nat Biotechnol 34:987-92
Rodriques, Samuel G; Marblestone, Adam H; Scholvin, Jorg et al. (2016) Multiplexed neural recording along a single optical fiber via optical reflectometry. J Biomed Opt 21:57003
Scholvin, Jorg; Kinney, Justin P; Bernstein, Jacob G et al. (2016) Close-Packed Silicon Microelectrodes for Scalable Spatially Oversampled Neural Recording. IEEE Trans Biomed Eng 63:120-30
Zhang, Yu Shrike; Chang, Jae-Byum; Alvarez, Mario Moisés et al. (2016) Hybrid Microscopy: Enabling Inexpensive High-Performance Imaging through Combined Physical and Optical Magnifications. Sci Rep 6:22691
Chen, Fei; Wassie, Asmamaw T; Cote, Allison J et al. (2016) Nanoscale imaging of RNA with expansion microscopy. Nat Methods 13:679-84
Adamala, Katarzyna P; Martin-Alarcon, Daniel A; Boyden, Edward S (2016) Programmable RNA-binding protein composed of repeats of a single modular unit. Proc Natl Acad Sci U S A 113:E2579-88
Kodandaramaiah, Suhasa B; Holst, Gregory L; Wickersham, Ian R et al. (2016) Assembly and operation of the autopatcher for automated intracellular neural recording in vivo. Nat Protoc 11:634-54
Chen, Fei; Tillberg, Paul W; Boyden, Edward S (2015) Optical imaging. Expansion microscopy. Science 347:543-8
Kinney, Justin P; Bernstein, Jacob G; Meyer, Andrew J et al. (2015) A direct-to-drive neural data acquisition system. Front Neural Circuits 9:46
Pak, Nikita; Siegle, Joshua H; Kinney, Justin P et al. (2015) Closed-loop, ultraprecise, automated craniotomies. J Neurophysiol 113:3943-53

Showing the most recent 10 out of 15 publications