Alexa H. Veenema, Ph.D. - US grants

The neuropeptide arginine-vasopressin (AVP) is involved in the regulation of diverse social behaviors in adulthood. However, it is less clear how the AVP system in the brain regulates social behaviors during the juvenile period. This project will elucidate the mechanisms by which AVP regulates social play and social novelty-preference in juvenile male and female rats. Complementary approaches will be used, including microdialysis, pharmacological manipulations, and neuronal activation, to elucidate interactions between AVP and GABA systems in the lateral septum and AVP-mediated alterations in neuronal activation in projection areas of the lateral septum. The results will provide new insights on the regulation of social interactions among juveniles, which are known to be critically important for development of social competence and socialization in mammals, including rodents and humans.

The research will be integrated with an education plan in which new initiatives will be developed to expose high school and undergraduate students, particularly those from minority and under-represented groups, to hands-on behavioral neuroscience research. The research and education plans will build a firm foundation for a lifetime of integrated contributions to behavioral neuroscience research and education. Research findings will be disseminated to the public through public lectures, publications, and a web site. The archiving, access, and sharing of data will be according to Boston College policies.

7. PROJECT SUMMARY Social recognition (the ability to discriminate between familiar and unfamiliar individuals) is essential for appro- priate and beneficial social interactions. Conversely, social recognition deficits are observed in autism spec- trum disorders (ASD). ASD is diagnosed early in life and shows a strong male-bias in incidence and symptom severity. This drives the need to understand the neural basis of social recognition and to study this in both sex- es and at an early age. The vasopressin (VP) and oxytocin (OT) systems are ideal candidates to study the neural basis of social recognition because they modulate social recognition in humans and animals, show sex and age differences in the brain, have been implicated in ASD, and emerge as potential drug targets in the treatment of social dysfunction. The long-term goal of this research is to reveal the neuronal mechanisms and pathways by which VP and OT regulate social recognition in both sexes and at both juvenile and adult ages. We will use rats as model organism because social recognition is well defined in rats and the VP and OT sys- tems are highly conserved across mammalian species. The overall hypothesis is that VP and OT systems function differently in both sexes and at both ages to regulate social recognition. In support, we showed that administration of VP into the lateral septum (LS) improves social recognition in juvenile females, but not in ju- venile males. Moreover, blockade of the VP V1a receptor (V1aR; main VP receptor in the brain) impaired so- cial recognition in adult males and females while it induced a preference to investigate a familiar rat over a novel rat in juvenile males and females. The objective is to determine how VP and OT in the LS regulate social recognition in sex- and age-specific ways. There are three independent specific aims that collectively will pro- vide insights into the mechanisms and pathways by which VP and OT regulate social recognition. Aim 1 will test the hypothesis that differential LS-VP release underlies sex and age differences in the regulation of social recognition. Aim 2 will test the hypothesis that OT regulates social recognition in sex- and age-specific ways. Aim 3 will test the hypothesis that VP and OT in the LS regulate social recognition via sex- and age-specific modulation of LS projection areas. We will use a comprehensive approach that includes in vivo microdialysis, microinjections, anatomical pathway tracing, mapping of neuronal responses, and behavioral analysis. This approach is innovative because this will be the first comprehensive study comparing neuropeptidergic control of social recognition between the sexes and at two life stages. The proposed research is significant because VP and OT regulate social recognition in humans and outcomes may therefore have translational potential for understanding sex and age differences in the roles of VP and OT in normal and abnormal social recognition in humans.

DESCRIPTION (provided by applicant): 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.