In the Technology Core, we develop, validate, and implement (in the real-world drug abuse-relevant setting of the Center Projects and collaborations), next-generation technologies for studying neural circuit structure- function relationships. We pay particular attention to integrative methods for crossing spatial scales for observation and manipulation, from single neuron-resolution during behavior, to brainwide analysis during behavior. The central goal is synergistic with the Training core but necessarily inverted in structure; the technologies developed and applied here, though demonstrated in the lab and standing on firm ground, are in earlier and unpublished stages, are equipment-intensive, and cannot at present be disseminated in the short- course Training Core model. Instead, the Technology Core staff will guide the direct local implementation of these new technologies for Center Aims across all four research projects. Technology Core staff will be engaged to visit and guide local implementation of these technologies, which include CLARITY-optimized light sheet microscopy (COLM), Frame-projected Independent-fiber Photometry (FIP), optoencephalography (OEG), and fast resonant-scanning two-photon (2P) circuit interrogation (2PRS) in behavior.
In Aim 1 we implement COLM. A number of CLARITY papers have emerged but imaging speed remained a bottleneck; however, we recently met this challenge with an enabling light-sheet method, COLM, which may open a new landscape for understanding the structural underpinnings of maladaptive drug-modulated behavior.
In Aim 2 we develop across Center Projects, FIP for truly simultaneous high-speed multi-site observation of genetically-specified neural activity traffic across the adult mammalian brain, suitable for quantifying abused-drug experience- triggered joint activity relationships among multiple brainwide projections and cell populations. Among other applications in the Center, FIP will be used for simultaneous recording of multiple independent axonal activity signals representing diverse projections of ventral tegmental area dopamine neurons, tracking previously inaccessible activity relationships among these circuit elements at high speed during distinct salient sensory experiences. Finally in Aim 3 we develop for Center Projects both 1) large-field of view (5mm diameter) volumetric microscopy for recording with near-cellular resolution the activity of a half million cells in superficial cortex of awake behaving rodents (OEG); and 2) true cellular-resolution imaging of hundreds of individual neurons within brain volumes during behavior (resonant-scanning 2PRS). These tools enable investigation of interactions between subpopulations within and across brain regions, unbiased identification of behaviorally relevant circuit dynamics and processing hierarchies, and (in combination with optogenetic stimulation) systematic causal analysis in abused-drug altered states.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Specialized Center (P50)
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Special Emphasis Panel (ZDA1)
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Stanford University
United States
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Wang, Xiao; Allen, William E; Wright, Matthew A et al. (2018) Three-dimensional intact-tissue sequencing of single-cell transcriptional states. Science 361:
Lovett-Barron, Matthew; Andalman, Aaron S; Allen, William E et al. (2017) Ancestral Circuits for the Coordinated Modulation of Brain State. Cell 171:1411-1423.e17