# Neuromodulatory control of collective circuit dynamics in C. elegans

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2021 · $455,727

## Abstract

Many animal behaviors are organized into long-lasting states, perhaps most strikingly in the sleep/wake
and emotional states that mammals display. However, the fundamental mechanisms that allow animals to
initiate, maintain and terminate these states are unknown. Biogenic amine and neuropeptide neuromodulators
are critical for the generation of behavioral states, but a mechanistic understanding of how neuromodulators act
on circuits to generate stable circuit-wide patterns of neural activity has been lacking, largely due to the
complexity of neuromodulation in mammalian circuits. We have chosen to tackle this problem using C. elegans,
a nematode whose nervous system consists of 302 neurons with a fully defined wiring diagram. We previously
characterized C. elegans movement patterns and showed that feeding animals transition between two stable
arousal states, roaming and dwelling. We characterized the neural circuit that generates roaming and dwelling
states, and found that two opposing neuromodulators, serotonin and the neuropeptide PDF, act on a defined
neural circuit to generate this bi-stable behavior: serotonin action on the circuit stabilizes dwelling states, while
PDF stabilizes roaming states. Now that we have defined a neuromodulatory circuit that generates persistent
behavioral states, we are poised to resolve several fundamental questions about neural circuit function and
organization. Here, we propose to dissect mechanisms of neural circuit persistence by examining how specific
neuromodulators reconfigure neural circuits to stabilize circuit-wide activity patterns that give rise to long-lasting
behavioral states. Resolving this question requires whole-circuit measurements of neural activity as animals
freely transition between states. Thus, we have already developed a new imaging technology that allows us to
simultaneously monitor the activity of every neuron in a circuit in freely-moving C. elegans animals. By combining
this imaging technology with genetic/optogenetic manipulations and new analysis/modeling methods, we will
illustrate a new multi-disciplinary approach that can be used to dissect the mechanisms by which collective neural
dynamics arise in a circuit. First, we will first identify the circuit-wide patterns of activity that define different
behavioral states (Aim 1). Second, we will perturb this system to examine how neuromodulators act on specific
neurons in the circuit to generate these stable circuit-wide patterns of activity (Aim 2). Finally, we will determine
how activity in this neuromodulatory circuit is altered by changes in the environment and, after simultaneously
recording the sensory neurons that feed into this circuit, we will develop a network model that describes how
noisy sensory inputs are transformed into a bi-stable behavioral state output (Aim 3). These studies will provide
new mechanistic insights into how neuromodulators orchestrate whole-circuit changes in activity to influence
behavior. By providin...

## Key facts

- **NIH application ID:** 10207798
- **Project number:** 5R01NS104892-05
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Steven Willem Flavell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $455,727
- **Award type:** 5
- **Project period:** 2017-09-25 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10207798

## Citation

> US National Institutes of Health, RePORTER application 10207798, Neuromodulatory control of collective circuit dynamics in C. elegans (5R01NS104892-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10207798. Licensed CC0.

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