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<p>Stress is a major risk factor for maladaptive processes such as pathological anxiety, which is highly prevalent in Tuberous Sclerosis Complex (TSC), a neurodevelopmental disorder caused by Tsc1/Tsc2 mutations. To investigate underlying mechanisms, we modeled Tsc2 haploinsufficiency in oxytocin receptor-expressing cells (OTRCs). Conditional deletion of Tsc2 in OTRCs induced hyperactivation of mTORC1 and PERK-mediated integrated stress response (ISR), impairing protein synthesis and suppressing medial prefrontal cortex (mPFC) circuits. Under chronic social isolation stress, male mutants exhibited anxiety-like behaviors, reduced motivation, and prefrontal hypoactivity, whereas females showed resilience to motivational deficits but diminished social preference. Pharmacological PERK inhibition, and OTRC-specific Rheb manipulation&#xa0;in mPFC, restored normative behavior and mPFC excitability, implicating the TSC–Rheb–PERK axis as a regulator of sex-specific stress vulnerability. These findings highlight integrated stress response modulation in OTRCs as a potential therapeutic strategy for anxiety linked to prefrontal dysfunction.</p>

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Prefrontal oxytocin receptor positive cells mediate stress-induced anxiety in tuberous sclerosis complex

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Olivia Tabaka,
  • Saheed Lawal,
  • Rodrigo Del Rio Triana,
  • Mian Hou,
  • Alexandra Fraser,
  • Andrew Gallagher,
  • Karen San Agustin Ruiz,
  • Maggie Marmarcz,
  • Matthew Dickinson,
  • Mauricio M. Oliveira,
  • Eric Klann,
  • Prerana Shrestha

摘要

Stress is a major risk factor for maladaptive processes such as pathological anxiety, which is highly prevalent in Tuberous Sclerosis Complex (TSC), a neurodevelopmental disorder caused by Tsc1/Tsc2 mutations. To investigate underlying mechanisms, we modeled Tsc2 haploinsufficiency in oxytocin receptor-expressing cells (OTRCs). Conditional deletion of Tsc2 in OTRCs induced hyperactivation of mTORC1 and PERK-mediated integrated stress response (ISR), impairing protein synthesis and suppressing medial prefrontal cortex (mPFC) circuits. Under chronic social isolation stress, male mutants exhibited anxiety-like behaviors, reduced motivation, and prefrontal hypoactivity, whereas females showed resilience to motivational deficits but diminished social preference. Pharmacological PERK inhibition, and OTRC-specific Rheb manipulation in mPFC, restored normative behavior and mPFC excitability, implicating the TSC–Rheb–PERK axis as a regulator of sex-specific stress vulnerability. These findings highlight integrated stress response modulation in OTRCs as a potential therapeutic strategy for anxiety linked to prefrontal dysfunction.