# Single-cell causality in origination, propagation, and resolution of drug-altered brain states

> **NIH NIH P50** · STANFORD UNIVERSITY · 2024 · $311,050

## Abstract

PROJECT SUMMARY (Project 1)
Here we implement a technology-driven approach to identify and control circuit dynamics underlying drug-
modulated 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 hydrogel-tissue chemistry including STARmap) 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
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 our population and projection-specific recording and intervention capability, 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 achieve single-cell resolution while maintaining map-like broad perspective,
during behavior and during exposure to drugs of abuse. Interventional tests for causality will be directly guided
by these observations, and will build upon both single-cell-resolution ensemble control and deep transcriptomic
analysis of those individual cells. 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.

## Key facts

- **NIH application ID:** 10917019
- **Project number:** 5P50DA042012-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Karl A. Deisseroth
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $311,050
- **Award type:** 5
- **Project period:** 2017-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917019

## Citation

> US National Institutes of Health, RePORTER application 10917019, Single-cell causality in origination, propagation, and resolution of drug-altered brain states (5P50DA042012-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10917019. Licensed CC0.

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