Social deficits are a hallmark feature of several psychiatric and neurodevelopmental disorders and are a core symptom of autism spectrum disorder. To date, behavioral therapies are the first line of intervention for treating impaired social behaviors, whereas pharmacological treatments have been ineffective at addressing this symptom domain. To inform treatment targets, there is an urgent need to understand the pathophysiology underlying social deficits. Several neural circuits and hormones involved in social behaviors have been identified and are conserved across species, e.g., the hypothalamic paraventricular nucleus and the release of the oxytocin peptide. Despite the wealth of behavioral and pharmacological studies implicating the paraventricular nucleus and oxytocin in social behavior, little is known about the effect of autism-associated mutations on the oxytocin system and whether malfunction in this system underlies social deficits in autism. Oxytocin is primarily synthesized by neurons in the paraventricular and supraoptic nuclei of the hypothalamus and is released peripherally to regulate physiological functions and centrally to modulate social behavior. Glutamatergic signaling is involved in the process of oxytocin release. Notably, mutations in the Shank3 gene, a high-risk gene for autism, perturb glutamatergic signaling in the hippocampus and striatum. However, the effect of Shank3 mutations on glutamatergic signaling and oxytocin release in the paraventricular nucleus has never been studied before. In this proposal, we study the effect of Shank3 mutations on the oxytocin system to ask how a Shank3 mutation in rats affect the activity of oxytocin neurons, glutamatergic signaling in the paraventricular nucleus, and the release of oxytocin at brain regions of social behavior. We also investigate whether the effect of Shank3 mutations on the oxytocin system underlies social behavior deficits. Our central hypothesis is that Shank3 mutations impair oxytocin release within the paraventricular nucleus and at brain regions of the social recognition circuit (Aim 1) by interfering with glutamatergic signaling and neural activity of oxytocin neurons in the paraventricular nucleus (Aim 2), leading to social recognition deficits (Aim 3). To this end, we will utilize a rat model with a Shank3 mutation and employ molecular, behavioral, and in vivo imaging experiments to capture alterations in neural activity of oxytocin neurons and identify impairments in oxytocin release during behavior. We will also employ viral-based approaches and chemo-genetic tools for neural-specific manipulations to determine causality between alteration in the oxytocin system and deficits in social behavior, caused by a Shank3 mutation. This study will lead to a clearer understanding of Shank3 function in the hypothalamic oxytocin system, which is part of a larger social brain circuit that could be targeted pharmacologically, genetically, or via circuit-specific non-invasive interventions to treat social behavior deficits in individuals with SHANK3 mutations and in individuals with autism that present similar brain alterations.
The proposed research is relevant to public health and to the NIH mission because it will lead to a circuit level understanding of fundamental brain mechanisms underlying social behavior, which may be impaired in psychiatric and neurodevelopmental disorders with social behavioral deficits. By leveraging the a rat model for autism spectrum disorder with a mutation in the Shank3 gene, the proposed research will also lead to a systems level understanding of Shank3 function in brain circuits of social behavior with the potential of identifying new targets for treatment. ! !
