2. Academic Validation
  3. Prefrontal oxytocin receptor positive cells mediate stress-induced anxiety in tuberous sclerosis complex

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

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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