Friday, July 26, 2024
7/26/2024
PROJECT SUMMARY Social play is a highly rewarding behavior and important for social skill development as has been demonstrated for human children and juvenile rats. Children with autism spectrum disorder (ASD) exhibit social play deficits, which contributes to their lifelong social dysfunction. ASD is more prevalent in males than in females, suggest- ing sex differences in the etiology of ASD. Developing effective means to restore social play in children with ASD will improve their lifelong social functioning, but this requires better understanding of the neural basis of social play and potential sex differences herein. Social deficits in ASD are associated with changes in the oxy- tocin (OXT) system and in the brain reward system, with both systems being critical for normal social function- ing. Furthermore, the OXT system is a potential drug target to improve social functioning in ASD patients. However, virtually nothing is known about OXT's role in social play. Our proposed research in rats aims to ad- vance understanding of the neural pathways by which OXT regulates social play in males and females. This is a first essential step to help inform sex-specific therapeutic strategies to effectively improve social play in chil- dren with ASD. Our central hypothesis is that OXT modulates the activity of reward-associated brain regions to regulate social play behavior in sex-specific ways. Specifically, we propose a role for paraventricular nucleus (PVN)-derived OXT in regulating social play by modulating the activity of OXT receptor (OXTR)-expressing neurons in the nucleus accumbens (NAc) that project to the ventral pallidum (VP). We further propose that this pathway is recruited sex-specifically. Based on strong preliminary data, we will test our novel concept that the PVNOXT→NAcOXTR→VP pathway mediates the sex-specific regulation of social play: In Aim 1, we will test the hypothesis that the PVNOXT→NAc pathway regulates social play and does so sex-specifically; In Aim 2, we will test the hypothesis that the NAcOXTR→VP pathway regulates social play and does so sex-specifically; In Aim 3, we will test the hypothesis that the same NAcOXTR neuron population that receives PVNOXT input projects to the VP and is sex-specifically activated during social play. These proposed studies will reveal a new neural circuit spanning 3 brain regions (PVN→NAc→VP) that sex-specifically modulates social play. Using newly developed genetic tools, namely an Oxtr-iCre rat line, we will be the first to examine the neural pathways by which OXT signaling regulates any behavior in rats. Our findings will significantly advance the field by providing the first evidence for the sex-specific involvement of the OXT system in regulating social play. Outcomes will help in- form the role of OXT in typical and atypical social play in human children, and will provide mechanistic insights into why ASD is more prevalent in males than in females.
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