# Neuromodulator signaling and activity in the C. elegans egg-laying circuit

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $616,225

## Abstract

Project Summary/Abstract
The long-term goal of this project is to delineate at an unprecedented level of precision how all the
neurotransmitter and neuropeptide signaling events within a model neural circuit together produce its dynamic
pattern of activity. Neural circuits are a basic unit of brain function and altered signaling within neural circuits can
disrupt circuit function to produce human brain diseases. To date, our understanding of such diseases remains
vague because we understand only a few individual features within each of the many different neural circuits
that have been studied. Therefore, our approach is to analyze all the signaling events within one simple neural
circuit, anticipating that this will yield new insights into how neural circuits in general work. This approach is
inspired by past successes in other areas of biology in which deep analysis of a simple model in a genetically
tractable organism (e.g. the lac operon in E. coli) led to conceptual breakthroughs that generalized to human
biology. Thus, we are intensely studying the simple egg-laying behavior circuit of C. elegans, in which we have
developed a powerful combination of genetic, optogenetic, chemogenetic, and Ca2+ imaging approaches that
provide unprecedented mechanistic insights into circuit function. This circuit alternates between ~20 minute
inactive states when eggs collect in the uterus and ~2.5 minute active states when eggs are laid. In past work,
we studied how the circuit turns on, and we now turn our focus to understanding how the circuit turns off. We
identified specific neurotransmitters and neuropeptides that signal through the heterotrimeric G protein Gαo to
turn off the circuit by antagonizing the Gαq signaling that turns the circuit on. Aim 1 uses biochemistry, genetics,
Ca2+ and fluorescent reporter imaging, and electrophysiology to test our hypothesis that Gαo directly activates a
G protein GTPase activator to terminate Gαq/Rho signaling and a diacylglycerol kinase to terminate Gαq/PLCBb
signaling, thus inhibiting neuron and muscle electrical excitability. Aim 2 uses genetics, Ca2+ imaging, and
electron microscopy to define structures and functions of the remaining uncharacterized components of the
circuit, including 1) PVW neurons, which we found branch over the egg-laying muscles and regulate egg laying;
and 2) gap junctions between these muscle cells. Aim 3 studies how mechanosensory feedback inhibits the
circuit after eggs are successfully laid. We discovered that specific neurons detect egg release, and that egg-
laying muscles appear to detect when fewer unlaid eggs remain in the uterus. We will use genetics, Ca2+ imaging,
and physiological approaches to study the mechanisms of this mechanosensory feedback inhibition of circuit
activity. The molecular, cellular, and circuit-level mechanisms we are defining that control activity of the C.
elegans egg-laying circuit are likely conserved and will inform our understanding of neural circuits i...

## Key facts

- **NIH application ID:** 10809349
- **Project number:** 2R01NS086932-09A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Kevin Michael Collins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $616,225
- **Award type:** 2
- **Project period:** 2014-09-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809349

## Citation

> US National Institutes of Health, RePORTER application 10809349, Neuromodulator signaling and activity in the C. elegans egg-laying circuit (2R01NS086932-09A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10809349. Licensed CC0.

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