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Rationale <p>Accelerated forgetting contributes substantially to memory deterioration in various neurological disorders in which inflammation is a prominent pathological hallmark. Inflammation typically impairs memory formation. Given that the neural mechanisms underpinning forgetting may be associated with that supporting memory formation, inflammation could be a key driver of accelerated forgetting. However, this assumption and its mechanistic basis have not been systematically examined.</p> Objectives <p>To determine whether lipopolysaccharide (LPS), a robust inducer of systemic inflammation, accelerates the forgetting of recognition memory, and whether the integrated stress response (ISR) plays a mechanistic role in this process.</p> Methods <p>Mice were trained based on two recognition memory paradigms and subsequently received vehicle, LPS, or LPS combined with the ISR inhibitor ISRIB during the memory retention interval. Sickness behavior was assessed by monitoring body weight and food intake. Memory performance was quantified using the exploration index reflecting novelty preference. Microglial and ISR activation in the hippocampus were evaluated via examining the expression of Iba1, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 (ATF4), respectively.</p> Results <p>LPS elicited marked sickness behaviors, accelerated the decay of previously acquired recognition memory, and triggered robust microglial and ISR activation in the hippocampus. ISRIB administration effectively reversed LPS-provoked microglial and ISR activation, and accelerated forgetting, while leaving sickness behaviors and memory retrieval unaffected.</p> Conclusions <p>LPS-elicited inflammation accelerates the forgetting of recognition memory, and ISR activation is involved in this effect, suggesting that ISR inhibition may provide a potential therapeutic target for inflammation-associated accelerated forgetting.</p>

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Integrated stress response inhibition rescues inflammation-associated accelerated forgetting of recognition memory in mice

  • 期刊论文

  • 发表日期：

    2026年3月23日

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  • Shi-Yan Liu,
  • Yi Zuo,
  • Xin Jin,
  • Xin Kuang,
  • Shao-Wen Tian

摘要

Rationale

Accelerated forgetting contributes substantially to memory deterioration in various neurological disorders in which inflammation is a prominent pathological hallmark. Inflammation typically impairs memory formation. Given that the neural mechanisms underpinning forgetting may be associated with that supporting memory formation, inflammation could be a key driver of accelerated forgetting. However, this assumption and its mechanistic basis have not been systematically examined.

Objectives

To determine whether lipopolysaccharide (LPS), a robust inducer of systemic inflammation, accelerates the forgetting of recognition memory, and whether the integrated stress response (ISR) plays a mechanistic role in this process.

Methods

Mice were trained based on two recognition memory paradigms and subsequently received vehicle, LPS, or LPS combined with the ISR inhibitor ISRIB during the memory retention interval. Sickness behavior was assessed by monitoring body weight and food intake. Memory performance was quantified using the exploration index reflecting novelty preference. Microglial and ISR activation in the hippocampus were evaluated via examining the expression of Iba1, phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α), and activating transcription factor 4 (ATF4), respectively.

Results

LPS elicited marked sickness behaviors, accelerated the decay of previously acquired recognition memory, and triggered robust microglial and ISR activation in the hippocampus. ISRIB administration effectively reversed LPS-provoked microglial and ISR activation, and accelerated forgetting, while leaving sickness behaviors and memory retrieval unaffected.

Conclusions

LPS-elicited inflammation accelerates the forgetting of recognition memory, and ISR activation is involved in this effect, suggesting that ISR inhibition may provide a potential therapeutic target for inflammation-associated accelerated forgetting.