# Cracking the neuromodulation code at single cell resolution

> **NIH NIH DP1** · JOHNS HOPKINS UNIVERSITY · 2020 · $1,146,250

## Abstract

Project Summary/Abstract
One of challenges in modern Neuroscience is to understand circuit mechanisms that lead to
complex behaviors. Our ability to monitor neuronal activity in vivo using genetically encoded
calcium indicators and various imaging/optogenetic techniques such as two-photon imaging and
channelrhodopsin have helped us define real-time changes in neuronal activity and the circuit
basis of behaviors. However, learning and behaviors cannot be solely explained by
electrophysiological properties of single neurons and their synaptic connectivity because they
are modulated by internal brain state. Therefore, we cannot fully understand diverse emotional
or behavioral reactions without understanding the internal brain state.
Neuromodulators have been suggested as key molecules that control brain state, but their
action to neurons has not been understood at cellular resolution. We have recently developed a
novel technique (named “iTango2”) that labels and manipulates neuromodulation-sensitive
neuronal populations with high spatiotemporal resolution. Using this iTango2 methodology, we
would like to dissect neuromodulator circuits at individual cell levels, and their physiological
implications related to complex behavior will be explored in this study. In the first aim, we will
examine how sparse dopamine projection in the premotor cortex contributes to cortical circuit
assembly, which may uncover cellular mechanisms of the asymmetric principle of cortical
neuronal connectivity. Second, we will dissect neuromodulation signaling at subcellular
resolution. This will be accomplished by creating a synapse version of iTango2, “Syn-iTango2”.
In order to identify potential cortical layer- or dendritic branch-specific mechanisms, we will
perform real-time monitoring of local dendritic activation triggered by neuromodulatory inputs in
brain slices as well as awake behaving animals, and concomitant structural changes such as
spine formation or enlargement will be examined. In the third aim, we would like to identify the
neuronal ensemble responsible for social interaction, one of the essential complex behaviors in
mammals. Since iTango2 links neuromodulation signals to gene expression, we will test the
sufficiency of identified circuits to social behavior. Last, we will build a large library of iTango2,
so that this approach becomes broadly useful to a variety of neuroscientists.
In summary, completion of this study will demonstrate fine scale of neuromodulation action in a
quantitative manner rather than a simple “ON” or “OFF” effect of neuromodulation. Monitoring
neuromodulatory effects and manipulating populations of cells with high spatial and temporal
resolution would dramatically increase our knowledge of the pathways that underlie vertebrate
animal behaviors.

## Key facts

- **NIH application ID:** 10003391
- **Project number:** 5DP1MH119428-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Hyungbae Kwon
- **Activity code:** DP1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,146,250
- **Award type:** 5
- **Project period:** 2018-09-10 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003391

## Citation

> US National Institutes of Health, RePORTER application 10003391, Cracking the neuromodulation code at single cell resolution (5DP1MH119428-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003391. Licensed CC0.

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