PROJECT SUMMARY Severe social impairment is a shared symptom of many neuropsychiatric illnesses. In particular, deficits in the ability to recognize and remember previously encountered individuals—often called social memory—can significantly compromise an individual’s ability to form and maintain social relationships, dramatically reducing quality of life. Among the brain regions associated with social impairment, the hippocampus is notable due to its essential role in social memory and its exceptional structural plasticity, including the continuous generation of new neurons in the dentate gyrus throughout adulthood. Harnessing naturally occurring structural plasticity in the hippocampus may be a valuable approach for stimulating neural circuits and restoring social memory function. Thus, the goal of this R01 proposal is to uncover the contribution of hippocampal structural plasticity to social memory circuits. Our published work demonstrated that adult-born neurons in the dentate gyrus are necessary for consolidating and/recalling social memories for conspecifics. Yet, the extent to which adult-born neurons are recruited to social memory traces and contribute selectively to social memory processes is undetermined. Adult-born neurons form multiple cellular connections within the hippocampus, including with CA2 neurons. While largely understudied, the CA2 region of the hippocampus has emerged as a critical hub for social memory function. We do not know whether adult-born neurons influence social memory circuits and function via their connections with CA2. In our preliminary studies using a mouse model of social dysfunction, the Shank3B KO mouse, we found impaired social memory along with hippocampal aberrations, including fewer adult-born neurons and diminished afferents from adult-born neurons to CA2 compared to wild-type littermates. We then used chemogenetics to activate CA2 neurons and the CA2-to-ventral CA1 pathway and were able to rescue social memory dysfunction in Shank3B KO mice, suggesting this circuitry as a pivotal intervention point for improving function. Here, we propose to use transgenic, chemogenetic, and pharmacologic manipulations combined with behavioral, histological, and in vivo electrophysiological analyses to test the hypothesis that afferent innervation of CA2 by adult-born neurons is critical in regulating social memory function, and that targeting this circuitry can alleviate social memory dysfunction. Specifically, we will elucidate the preferential recruitment of adult-born neurons to social memory engrams and their selective contribution to social memory function (Aim 1), identify the influence of adult-born neuron afferents to CA2 on CA2 oscillatory activity and social memory function (Aim 2), and explore enhancing hippocampal adult-born neuron circuitry to improve social memory deficits in Shank3B KO mouse (Aim 3). These studies will provide a mechanistic understanding of how adult-born neurons impact social memory ...