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<p>While memory regulation is predominantly understood as autonomous to neurons, factors outside the brain can also affect neuronal function. In <i>Caenorhabditis elegans</i>, the insulin/IGF-1-like signaling (IIS) pathway regulates longevity, metabolism and memory: long-lived <i>daf-2</i> insulin/IGF-1 receptor mutants more than double memory duration after a single training session, and it was assumed that memory regulation was strictly neuronal. However, here we show that degradation of DAF-2 in the hypodermis also greatly extends memory, via expression of the diffusible Notch ligand, OSM-11, which in turn activates Notch signaling in neurons. Single-nucleus RNA sequencing of neurons revealed increased expression of CREB and other memory genes. Furthermore, in aged animals, activation of the hypodermal IIS–Notch pathway as well as OSM-11 overexpression rescue both memory and learning via CREB activity. Thus, insulin signaling in the liver-like hypodermis non-autonomously regulates neuronal function, providing a systemic connection between metabolism and memory through IIS–Notch–CREB signaling from the body to the brain.</p>

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Body-to-brain insulin and Notch signaling regulates memory through neuronal CREB activity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Shiyi Zhou,
  • Katherine E. Novak,
  • Rachel Kaletsky,
  • Yifei Weng,
  • Jonathan St. Ange,
  • Morgan E. Stevenson,
  • Erik Toraason,
  • Yanping Zhang,
  • Wenhong Zhang,
  • Meng-Qiu Dong,
  • Coleen T. Murphy

摘要

While memory regulation is predominantly understood as autonomous to neurons, factors outside the brain can also affect neuronal function. In Caenorhabditis elegans, the insulin/IGF-1-like signaling (IIS) pathway regulates longevity, metabolism and memory: long-lived daf-2 insulin/IGF-1 receptor mutants more than double memory duration after a single training session, and it was assumed that memory regulation was strictly neuronal. However, here we show that degradation of DAF-2 in the hypodermis also greatly extends memory, via expression of the diffusible Notch ligand, OSM-11, which in turn activates Notch signaling in neurons. Single-nucleus RNA sequencing of neurons revealed increased expression of CREB and other memory genes. Furthermore, in aged animals, activation of the hypodermal IIS–Notch pathway as well as OSM-11 overexpression rescue both memory and learning via CREB activity. Thus, insulin signaling in the liver-like hypodermis non-autonomously regulates neuronal function, providing a systemic connection between metabolism and memory through IIS–Notch–CREB signaling from the body to the brain.