# Investigating neuropeptide signals that slow cognitive aging in C. elegans

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2024 · $48,974

## Abstract

ABSTRACT
The average life expectancy has nearly doubled in the last century, leading to increased rates of cognitive decline
in aged populations. Therefore, it is critical to identify mechanisms that restore memory function with age. One
such mechanism is activation of cAMP response element-binding protein (CREB), which is a highly conserved
transcriptional regulator of long-term associative memory (LTAM). Across species, increased CREB activity is
associated with enhanced memory with age, but the mechanisms underlying this phenomenon are not well-
understood. Recent research in C. elegans suggests that enhanced neuropeptide signaling from a single sensory
neuron, the AWC, promotes learning and extends CREB-dependent LTAM in young and aged animals.
Specifically, extended memory required 1.) neuropeptide secretion from the AWC and 2.) CREB activity in the
AIM interneuron, which is the established site of memory activity in C. elegans. These results indicate that
increased AWC neuropeptide signaling may boost cognitive healthspan in C. elegans. However, the memory-
promoting neuropeptide(s) and whether their mechanism of action regulates learning or CREB-dependent
memory is unknown. Furthermore, AWC neuropeptide signals regulate a variety of neuronal phenotypes that
decline with age, including chemotaxis, locomotory behaviors, and egg-laying. Interestingly, we have found that
increased AWC peptide release significantly reduces the rate of matricidal egg hatching—a neuronally-regulated
phenotype that occurs more frequently in aged animals—suggesting AWC peptide signaling also promotes the
healthspan of neuronal circuitry. Although, how AWC peptide signaling regulates the healthspan of other
neuronal phenotypes has yet to be investigated. From these findings, we hypothesize that AWC-specific
neuropeptide signaling promotes learning and CREB-dependent memory with age and extends neuronal
healthspan in C. elegans. We will test this hypothesis by performing a highly targeted RNAi screen to identify
AWC neuropeptide signals that promote learning, CREB activity in the AIM, and LTAM. Then, we will identify the
corresponding receptors, which are largely conserved, druggable targets that may be tested in higher organisms.
Finally, we will perform a battery of AWC-driven behaviors to determine the role of AWC neuropeptide signaling
in extending neuronal healthspan phenotypes. Overall, this research will provide insight into the molecular
underpinnings of age-related cognitive decline, potentially leading to novel therapeutic targets for cognitive
impairment in higher organisms.

## Key facts

- **NIH application ID:** 10915446
- **Project number:** 5F31AG081095-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Emily Jean Leptich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-07 → 2025-08-06

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915446

## Citation

> US National Institutes of Health, RePORTER application 10915446, Investigating neuropeptide signals that slow cognitive aging in C. elegans (5F31AG081095-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10915446. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*