Award Abstract # 1707261
NeuroNex Technology Hub: Integrated Circuit Cracking (ICC) with Linked Tools for Diverse Systems

NSF Org: DBI
Division of Biological Infrastructure
Recipient: THE LELAND STANFORD JUNIOR UNIVERSITY
Initial Amendment Date: July 31, 2017
Latest Amendment Date: July 30, 2021
Award Number: 1707261
Award Instrument: Cooperative Agreement
Program Manager: Reed Beaman
DBI
 Division of Biological Infrastructure
BIO
 Directorate for Biological Sciences
Start Date: December 1, 2017
End Date: November 30, 2022 (Estimated)
Total Intended Award Amount: $3,680,000.00
Total Awarded Amount to Date: $9,200,000.00
Funds Obligated to Date: FY 2017 = $1,840,000.00
FY 2019 = $1,840,000.00

FY 2020 = $1,840,000.00

FY 2021 = $3,680,000.00
History of Investigator:
  • Karl Deisseroth (Principal Investigator)
    deissero@stanford.edu
  • Mark Schnitzer (Co-Principal Investigator)
Recipient Sponsored Research Office: Stanford University
450 JANE STANFORD WAY
STANFORD
CA  US  94305-2004
(650)723-2300
Sponsor Congressional District: 16
Primary Place of Performance: Stanford University
1050 Arastradero Rd., Building B
Palo Alto
CA  US  94304-1334
Primary Place of Performance
Congressional District:
16
Unique Entity Identifier (UEI): HJD6G4D6TJY5
Parent UEI:
NSF Program(s): RESEARCH RESOURCES,
Cross-BIO Activities
Primary Program Source: 01001718DB NSF RESEARCH & RELATED ACTIVIT
01001819DB NSF RESEARCH & RELATED ACTIVIT

01001920DB NSF RESEARCH & RELATED ACTIVIT

01002021DB NSF RESEARCH & RELATED ACTIVIT

01002122DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 8089, 8091
Program Element Code(s): 110100, 727500
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.074

ABSTRACT

This NeuroNex Technology Hub, based at Stanford and the Salk Institute in California, will profoundly advance the understanding of the brain by developing technologies to study the brain's structure and function. The investigators will develop new approaches to understand how the individual components that make up the nervous system operate during behavior, and indeed cause behavior. The team will merge principles from genetics, physics, optics, engineering, and biology, to build and disseminate methodology, instrumentation, and analytics that enable targeting and control of individual kinds of brain cells, and the technology developed will be taught via hands-on training available to the scientific community. The outcome will be a broadly-applicable platform for discovering how neural circuit activity gives rise to complex cognitions and behaviors in the brain, which is essential to understand how the nervous stem fails to operate well in neurological and psychiatric diseases. The structure of the NeuroNex Training Core is designed to drive the participation of investigators across the spectrum of background and demography, including junior investigators and students as well as women and other underrepresented groups in STEM.

Current understanding of brain function at the cellular network level is limited by the lack of integrative tools that (in the same individual organism) can be used for molecularly defining neural circuit components, for tracing local and global wiring of those same circuit components, and for observing and controlling activity in those same circuit components during precisely controlled and quantified behaviors. This integration, or "datastream linking", will fundamentally advance knowledge but is an enormous practical and intellectual challenge. This NeuroNex Technology Hub will 1) address this challenge with molecular, genetic and optical tools while also developing computational methods to discover the underlying natural and causal structural and dynamical motifs; 2) do so in a vertically-linked fashion so that all technologies built are mutually compatible in the same nervous system at the same time; 3) do so in a horizontally-linked fashion, so that the technologies built are suitable for primate rat, mouse, fly, and diverse fish species; 4) engage in outreach, training, and dissemination, open for broadest impact to the entire NSF community throughout the program. This teaching will leverage our current state-of-the-art methods and educational infrastructure, and will advance alongside the technology development and integration.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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(Showing: 1 - 10 of 38)
Allen W, DeNardo LA "Thirst-associated preoptic neurons encode an aversive motivational drive" Science , 2017 Citation Details
Allen, WE and Chen, MZ and Pichamoorthy, N and Tien, RH and Pachitariu, M and Luo, L and Deisseroth, K. "Thirst regulates motivated behavior through modulation of brainwide neural population dynamics." Science , 2019 Citation Details
Allen, William E. and DeNardo, Laura A. and Chen, Michael Z. and Liu, Cindy D. and Loh, Kyle M. and Fenno, Lief E. and Ramakrishnan, Charu and Deisseroth, Karl and Luo, Liqun "Thirst-associated preoptic neurons encode an aversive motivational drive" Science , v.357 , 2017 10.1126/science.aan6747 Citation Details
Beier, KT and Gao, XJ and Xie, S and DeLoach, KE and Malenka, RC and Luo, L. "Topological Organization of Ventral Tegmental Area Connectivity Revealed by Viral-Genetic Dissection of Input-Output Relations." Cell reports , 2019 Citation Details
Chen, Ritchie and Gore, Felicity and Nguyen, Quynh-Anh and Ramakrishnan, Charu and Patel, Sneha and Kim, Soo Hyun and Raffiee, Misha and Kim, Yoon Seok and Hsueh, Brian and Krook-Magnusson, Esther and Soltesz, Ivan and Deisseroth, Karl "Deep brain optogenetics without intracranial surgery" Nature Biotechnology , 2020 https://doi.org/10.1038/s41587-020-0679-9 Citation Details
DeNardo, L.A. and Liu, C.D. and Allen, WE and Adams, EL and Friedmann, D and Fu, L. and Guenthner, CJ and Tessier-Lavigne, M and Luo, L. "Temporal evolution of cortical ensembles promoting remote memory retrieval" Nature Neuroscience , 2019 Citation Details
DeNardo, LA and Liu, CD and Allen, WE and Adams, EL and Friedmann, LSF and Guenthner, CJ and Tessier-Lavigne, M and Luo, L. "Temporal evolution of cortical ensembles promoting memory retrieval." Nature Neuroscience , 2019 Citation Details
Faulkner, Regina L. and Wall, Nicholas R. and Callaway, Edward M. and Cline, Hollis T. "Application of Recombinant Rabies Virus to Xenopus Tadpole Brain" eneuro , v.8 , 2021 https://doi.org/10.1523/ENEURO.0477-20.2021 Citation Details
Fenno, Lief E. and Ramakrishnan, Charu and Kim, Yoon Seok and Evans, Kathryn E. and Lo, Maisie and Vesuna, Sam and Inoue, Masatoshi and Cheung, Kathy Y.M. and Yuen, Elle and Pichamoorthy, Nandini and Hong, Alice S.O. and Deisseroth, Karl "Comprehensive Dual- and Triple-Feature Intersectional Single-Vector Delivery of Diverse Functional Payloads to Cells of Behaving Mammals" Neuron , v.107 , 2020 https://doi.org/10.1016/j.neuron.2020.06.003 Citation Details
Girasole, Allison E. and Lum, Matthew Y. and Nathaniel, Diane and Bair-Marshall, Chloe J. and Guenthner, Casey J. and Luo, Liqun and Kreitzer, Anatol C. and Nelson, Alexandra B. "A Subpopulation of Striatal Neurons Mediates Levodopa-Induced Dyskinesia" Neuron , v.97 , 2018 10.1016/j.neuron.2018.01.017 Citation Details
Gradinaru V, Treweek J "Hydrogel-Tissue Chemistry: Principles and Applications" Annual review of biophysics , 2018 Citation Details
(Showing: 1 - 10 of 38)

PROJECT OUTCOMES REPORT

Disclaimer

This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

Supported by the NSF NeuroNex program, the Integrated Circuit Cracking NeuroNex Technology Hub has built and disseminated an integrated approach for molecularly defining, tracing local and global wiring, and observing and controlling activity of the same neural circuit components during precisely controlled and quantified behaviors.

 

Imaging brain activity across regions and species

 

Led by Dr. Mark Schnitzer’s lab (Stanford University), we created and applied several technologies for imaging brain activity to discover large-scale neural circuit dynamics and coding properties. New techniques include multi-armed, robotic methods for two-photon microscopy across multiple brain areas; a two-photon multi-laser beam mesoscope for imaging and manipulating neural activity across large contiguous tissue regions of mammalian neocortex; robotic, automated experimentation with 1000 Drosophila fly subjects per day; voltage-imaging for visualizing spiking patterns of genetically or projection -identified neuron-types in awake behaving flies or mammals. We have widely disseminated these approaches, including new voltage indicators and fly lines at publicly accessible repositories. These innovations enabled first studies of visual processing at cellular resolution across the entire visual cortex in mice performing visual discrimination and voltage-imaging studies of fly learning and memory, finding antagonistic interactions between short- and long-term memory traces.

 

Quantification of brain wiring of molecularly defined cell types

 

Spearheaded by Dr. Ed Callaway’s lab (The Salk Institute), we developed and refined technologies for measuring connections between cell types in the brain, including connections a neuron receives from other cells (retrograde transsynaptic labeling) or that it provides to other cells (anterograde transsynaptic labeling). We have developed cell-type specific retrograde methods based on genetically modified rabies virus that have been widely adopted by many labs around the world. Here we characterized the nature of viral spread between synaptically connected neurons, finding that connections are labeled with the same probability regardless of the cell type that the virus is used to infect or of the location of synapses on the cell’s dendritic processes. We also developed a new cell-type specific and monosynaptically restricted anterograde transsynaptic tracer based on genetically modified HSV; it can trace, across the entire brain, all the outputs from cell types of interest. This development adds a valuable component to the tool arsenal for molecular and viral dissection of brain circuits.

 

Linking brain activity to wiring of molecularly defined cell types

 

In efforts led by Dr. Liqun Luo’s lab (Stanford University), we have further developed upon techniques for tracing input and output relationships of specific neuron types and of “TRAPing” neurons activated by a specific experience or behavior for further interrogation—in multiple neural circuits. We have combined these techniques as well as methods to investigate all expressed genes within individual neurons to obtain new insights into the organization, function, and evolution of these circuits. We have broadly disseminated these techniques and reagents. For example, more than 2000 transgenic mice we developed that enable researchers to “TRAP” active neurons have been distributed to other researchers to investigate diverse neurobiological questions, resulting in many publications. 

 

Broadly enabling integrated circuit cracking

 

We developed and integrated large-scale neural recording methods to study circuit dynamics of diverse behaviors across species (mouse, fly, zebrafish) with targetable and quantifiable viral tracing of neural connectivity.  To gain causal understanding of circuit mechanisms, in efforts led by Dr. Karl Deisseroth’s lab, we developed potent optogenetic tools and novel optical technologies to record and manipulate specific cell populations of interest defined not only genetically, but also both functionally and spatially at the cellular level, including deep in the mammalian brain and across large regions. Applying these approaches revealed causal impacts of functional subnetworks on feeding, social, reward and sensory behaviors and corresponding brain dynamics.  To enable intersectional genetic access to diverse cell types, we developed upon and broadly shared several INTRSECT constructs that integrate tools for recording and manipulating brain activity. To uncover rich transcriptomic information about brain cell types, we developed and refined 3D intact-tissue RNA sequencing of single-cell transcriptional states, termed STARmap, incorporating hydrogel-tissue chemistry, targeted signal amplification, and in situ sequencing.  

 

Wide dissemination

 

Led by Dr. Deisseroth’s lab and encompassing all the program’s labs, we have shared molecular tools with well over 1,400 laboratories, initiated 120 collaborations with unpublished constructs, and deposited several hundred reagents at publicly accessible repositories. We have trained many hundreds of participants across career stages and backgrounds in nearly 70 workshops and courselets covering tools as they are developed including optogenetics, tissue clearing, fiber-photometry, genetically-targeted chemical assembly, and transcriptomics.

 

This comprehensive technology suite for probing and manipulating molecularly defined brain cell-type circuitry across species establishes a broadly enabling approach for integrated circuit cracking.  Following from many studies within our labs and broadly through collaborations, shared constructs, datasets, training and workshops we will build upon and share this integrated approach to help uncover circuit-level insights in diverse behaviors and disorders, with potentially major impacts on neural circuits research.

 


Last Modified: 04/28/2023
Modified by: Karl A Deisseroth

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