Research Projects

Approaching a friend and avoiding a foe involves social cognitive abilities, which is deficient in Autism Spectrum Disorder (ASD) – a neurodevelopmental condition with growing global prevalence. Recent preclinical reports including that by the PI (PMID38952926,38574475) indicate that discrimination of social safety from social threat involves neuropeptides like arginine-vasopressin (AVP). AVP improves general social cognition in ASD subjects, but could it also improve social cognition in aversive situations? Thus, we propose to test the efficacy of postnatal AVP therapy in improving social fear/safety discrimination (SF/SD) in a preclinical model of autism. Pregnant mice will be exposed to environmentally-relevant levels of di(2-ethylhexyl) pthalate (DEHP), an endocrine disruptor whose body burden is associated with ASD occurrence. Preliminary results confirm that DEHP-exposure delays development and impairs social and non-social cognition. Aversive social cognition will be quantified with a novel SF/SD task reported by the PI (PMID38574475) with and without AVP-therapy after DEHP-exposure. Finally, in vivo pharmacology and chemogenetics targeting hypothalamic AVP neurons and AVPr1b-positive dorsal CA2 neurons will interrogate a specific role of this circuit in ASD symptom and recovery. Insights into the understudied AVPr1b could open new avenues of vasopressin-therapy in autism. Objectives: 1. Validate environmentally-relevant DEHP exposure (DEHP-env) as an animal model of ASD (objective partially completed) 2. SF/SD task (PMID:38574475) in DEHP-env, followed by mapping of immediate-early gene expression in Hypothalamic AVP-neurons and AVPr1b-expressing dCA2 neurons (with relevant controls). 3. Postnatal AVP-treatment in DEHP-env pups (with relevant controls). 4. Mechanistic dissection of AVP/AVPr1b in hypothalamus-CA2 circuit with in vivo pharmacology and chemogenetics. Hypothesis: Impaired SF/SD in DEHP-env mice can be corrected with early postnatal treatment with AVP, by correcting AVP/AVPr1b action in the hypothalamus-CA2 circuit. Main experiments • In pups: neurodevelopmental milestones, social interaction; in young adults: novel object recognition, social interaction test [Obj1] • At 8 weeks, SF/SD test with cFos-mapping in hypothalamic AVP and CA2 AVPr1b neurons (immunofluorescence) [Obj2] • Postnatal AVP treatment, with SF/SD test and circuit activation mapping [Obj3] • Targeted chemogenetics and AVPr1b pharmacology [Obj4] Significance: This would be the first evidence of AVP therapy in improving aversive social cognition in ASD with potential to improve quality of life. AVP/AVPr1b with hippocampal imaging emerges as new biomarkers for ASD detection, and possibilities to patent and commercialize novel AVP-receptor modulators for therapy. DEHP-env establishes a new, clinically-relevant, non-genetic ASD model, with findings having potential to strongly influence sustainable development goals via public sensitization.