Aberrant TSC-Rheb axis in Oxytocin receptor+ cells mediate stress-induced anxiety.
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
Author Information
Olivia Tabaka: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Saheed Lawal: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Rodrigo Del Rio Triana: Center for Neural Science, New York University, New York, NY 10003.
Mian Hou: Center for Neural Science, New York University, New York, NY 10003.
Alexandra Fraser: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Andrew Gallagher: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Karen San Agustin Ruiz: Center for Neural Science, New York University, New York, NY 10003.
Maggie Marmarcz: Center for Neural Science, New York University, New York, NY 10003.
Matthew Dickinson: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Mauricio M Oliveira: Center for Neural Science, New York University, New York, NY 10003.
Eric Klann: Center for Neural Science, New York University, New York, NY 10003.
Prerana Shrestha: Department of Neurobiology & Behavior, Stony Brook University, Stony Brook, NY 11794.
Stress is a major risk for the onset of several maladaptive processes including pathological anxiety, a diffuse state of heightened apprehension over anticipated threats. Pathological anxiety is prevalent in up to 59% of patients with Tuberous Sclerosis complex (TSC), a neurodevelopmental disorder (NDD) caused by loss-of-function mutations in genes for Tuberin () and/or Hamartin () that together comprise the eponymous protein complex. Here, we generated cell type-specific heterozygous knockout of in cells expressing oxytocin receptor (OTRCs) to model pathological anxiety-like behaviors observed in TSC patient population. The stress of prolonged social isolation induces a sustained negative affective state that precipitates behavioral avoidance, often by aberrant oxytocin signaling in the limbic forebrain. In response to social isolation, there were striking sex differences in stress susceptibility in conditional heterozygote mice when encountering situations of approach-avoidance conflict. Socially isolated male mutants exhibited behavioral avoidance in anxiogenic environments and sought more social interaction for buffering of stress. In contrast, female mutants developed resilience during social isolation and approached anxiogenic environments, while devaluing social interaction. Systemic and medial prefrontal cortex (mPFC)-specific inhibition of downstream effector of TSC, the integrated stress response (ISR), rescued behavioral approach toward anxiogenic environments and conspecifics in male and female mutant mice respectively. Further, we found that deletion in OTRCs leads to OTR-signaling elicited network suppression, i.e., hypofrontality, in male mPFC, which is relieved by inhibiting the ISR. Our findings present evidence in support of a sexually dimorphic role of prefrontal OTRCs in regulating emotional responses in anxiogenic environments, which goes awry in TSC. Our work has broader implications for developing effective treatments for subtypes of anxiety disorders that are characterized by cell-autonomous ISR and prefrontal network suppression.
