In mice, removing a gene (Tsc2) from brain cells that have oxytocin receptors makes those cells overactive and triggers a stress response that leads to anxiety, especially in males under social isolation. Blocking part of that stress response (PERK) or tweaking a related protein (Rheb) in the prefrontal cortex can reverse the anxiety and restore normal brain activity. The study shows that oxytocin‑receptor cells are a key link between stress, anxiety, and a cellular pathway called mTORC1‑PERK.

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.