Work

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

Year: 2025

Type: article

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. Mechanistic studies in a mouse model of tuberous sclerosis complex reveal that heightened integrated stress response in oxytocin receptor positive neurons disrupts prefrontal cortex function and produces sex-specific anxiety behaviors under social isolation.

Source: Communications Biology

DOI: 10.1038/s42003-025-09193-3