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

  • Commun Biol. 2025 Nov 20;8(1):1789. doi: 10.1038/s42003-025-09193-3.
Olivia Tabaka  #  1 ,  Saheed Lawal  #  1 ,  Rodrigo Del Rio Triana  2 ,  Mian Hou  2 ,  Alexandra Fraser  1  3 ,  Andrew Gallagher  1 ,  Karen San Agustin Ruiz  2  4 ,  Maggie Marmarcz  2 ,  Matthew Dickinson  1 ,  Mauricio M Oliveira  2 ,  Eric Klann  5 ,  Prerana Shrestha  6
Affiliations
  • 1. Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, USA.
  • 2. Center for Neural Science, New York University, New York, NY, USA.
  • 3. Program in Neuroscience, Harvard University, Boston, MA, USA.
  • 4. Gene Therapy Team, Allen Brain Institute, Seattle, WA, USA.
  • 5. Center for Neural Science, New York University, New York, NY, USA. [email protected].
  • 6. Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY, USA. [email protected].
  • # Contributed equally.
PMID: 41266529 DOI: 10.1038/s42003-025-09193-3
Abstract

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.

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