Neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders represent a substantial burden to our public health system, affecting around 15% of children in the United States. Attempts to treat these disorders have proven largely unsuccessful, in part due to a lack of understanding of developmental pathways linking a diverse range of genetic and environmental risk factors with clinical phenotypes. Social behavior is commonly dysregulated in neurodevelopmental disorders, yet little is known about the neural mechanisms governing social behavior development. Appropriate adult social behavior likely relies on experience-dependent maturation of specific neuronal circuits and underlying changes in chromatin organization during key developmental windows. This represents a challenge to traditional approaches in neuroepigenetics, given that virtually all epigenomic approaches are cross-sectional, providing snapshots of genome function for a single time point. In this proposal, we leverage mouse models to bridge novel in vivo real time imaging of specific cell populations across development with epigenomic approaches, to allow, in a cell-type specific manner, retrospective assessment of social experience-dependent chromatin reorganization occurring during a social critical window in the developing prefrontal cortex (PFC). Our pilot data demonstrate an essential role for parvalbumin positive interneurons (PVIs) in PFC in regulating adult social behavior, as well as a necessity of juvenile social experience in shaping their proper activation in adult. However, it is unknown how social experience during development alters adult functioning of PFC-PVIs. Our approach will use fiber photometry to monitor activity of PVIs across development, both in the presence and absence of juvenile social experience. We will also employ vector constructs for transient expression, specifically within PFC-PVIs, of bacterial DNA adenine methyltransferase (Dam) fused with laminb1, a core component of the nuclear lamina, a protein network at the nuclear periphery that provides both structural support and regulates gene expression. This approach will allow us to explore how nuclear laminar-genomic changes associated with social experience during a critical window correlate with both cell type specific transcriptional, and in vivo activity changes in adult mice. We will take both a retrospective as well as traditional cross-sectional approach, to study how development of PVIs is affected by social experience. !
This proposal will use novel technologies in the brain to identify neuroepigenetic and cellular maturation mechanisms guiding response to social experience during critical windows of social behavior development in mice. Insight from findings in this proposal will promote the development of more effective and targeted therapies for neurodevelopmental disorders with social deficits.
