Here we implement a technology-driven approach to identify and control circuit dynamics underlying drug- modulated social and nonsocial behaviors, in contexts carrying reward and risk. We apply technology representing a major alignment of opportunity for drug abuse research (optoencephalography or OEG, frame- projected independent-fiber photometry or FIP, and CLARITY-optimized lightsheet microscopy or COLM) which allow not only observation and control of genetically-defined circuitry, but multiple circuit elements simultaneously and independently-- before, during and after behaviors in the drug-altered state.
In Aim 1, we begin at the broadest (brainwide) scale in awake rodents, to identify key players and principles in unbiased fashion, while maintaining circuit element-specificity for observation and control of activity. Technologically, Aim 1 experiments will include optogenetically-driven precise pulse patterns targeted to specific circuits and projections, as well as rapid and quantitative COLM- or ofMRI- based assessment of brainwide activity patterns. These initial unbiased global assessments will powerfully inform and focus more spatially-restricted investigations in Aims 2 and 3 that resolve essential features of acutely altered states.
In Aim 2 we operate at much higher spatial and temporal resolution, the next step toward detailed elucidation of causal circuit dynamics in the acutely drug-altered state. For the same drug and behavioral conditions in Aim 1, now quantitatively guided at the individual-animal level in terms of neuronal activity levels to be targeted using the population and projection-specific recording capability of FIP, we play-in patterns of population and projection activity to test causal impact on behavior. And in Aim 3, we leverage the highest-resolution of our new methods, that nonetheless maintain broad perspective. We are now able to image (with OEG as well as resonant-scanning two-photon microscopy) large volumes of brain and quantify high-speed dynamical activity patterns that are cell type-specific, approaching single-cell resolution while maintaining map-like brainwide perspective, during behavior and during exposure to drugs of abuse. Interventional tests for causality will be directly guided by these observations. As described below, we have already observed highly specific cortical activity patterns in response to subanaesthetic ketamine doses, which here will be extended to the same drug and behavioral conditions pertaining to Aims 1 and 2. This precise observation and control of distinct neural circuit pathways is tightly intertwined with the research programs described in Projects 2-4, and the Technology and Training Cores. Together, these experiments in Project 1 will test versatile, powerful new circuit-dynamics tools for use in the NIDA Center and for the drug abuse community more broadly, and will also apply these tools to deepen our understanding of acute or chronically-altered drug altered states, and of the brain itself as a dynamical system.

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
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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