Social play activities during childhood and adolescence are important for the development of social skills needed throughout life. Social play is a highly rewarding activity and is modulated by the mesocorticolimbic dopamine system. Social play deficits are a core symptom of neurodevelopmental disorders such as autism spectrum disorders (ASD). ASD and other neurodevelopmental disorders further show robust sex differences in incidence, symptom severity, and treatment responses. The vasopressin (VP) system is important for the regulation of social behaviors, is sexually dimorphic (males have more VP than females), shows abnormalities in ASD, and emerges as potential drug target in the treatment of social dysfunction. Understanding how VP regulates social behaviors during development and in both sexes is therefore essential. The long-term goal of this research is to reveal the neural circuitry by which VP regulates social play in both sexes. We use rats as model organism because social play is well defined in rats and the sexually dimorphic VP system is highly conserved across mammalian species. The overall hypothesis is that the LS-VP system is involved in sex- specific regulation of social play via its interactions with the brai reward system. In support, we showed that blockade of the VP V1a receptor (V1aR; main VP receptor in the brain) in the lateral septum (LS) enhances social play in males, but decreases it in females. This suggests that VP released in the LS inhibits social play in males, but stimulates social play in females. The objective is to identify the sex-specific neuronal mechanisms and the interaction of VP with the brain reward circuitry in the regulation of social play in juvenile rats We will build on these findings and aim to identify the mechanisms in the LS by which VP modulates social play in sex-specific ways (Aim 1) and determine whether VP acts through the LS-VTA pathway to modulate social play in sex-specific ways (Aim 2). The two independent specific aims will collectively reveal how the LS- VP system modulates major neurotransmitter systems in the LS and in the ventral tegmental area (VTA, site of origin of the mesocorticolimbic dopamine system) to regulate social play in sex-specific ways.
Aim 1 will test the hypothesis that VP mediates sex differences in LS neuronal activity during social play.
Aim 2 will test the hypothesis that VP mediates sex differences in the LS-VTA pathway during social play. This proposal is innovative because it will identify sex-specific neural mechanisms underlying the regulation of behavior, and it will reveal the involvement of the LS-VTA pathway in social reward behavior, and it will use a comprehensive multidisciplinary approach to examine the LS-VP system and its interactions with the VTA system in a unique and integrated way. The proposed research is significant because outcomes will be informative for understanding the potential role of VP in sex-specific regulation of typical and atypical social play in children.
The proposed research is relevant to public health because knowledge about sex-specific regulation of social play by vasopressin will advance our understanding of sex-specific regulation of behavior and will be informative for the social play deficits and the sex-biases in incidence, symptom severity, and treatment responses in social disorders, like autism spectrum disorders. This knowledge may also be informative for therapeutic uses of neuropeptidergic agents in the treatment of social dysfunction. The proposed research is relevant to the mission of NIMH to transform the understanding and treatment of mental illnesses.
