Abstract There is increasing evidence that alterations in myelin contribute to cognitive and behavioral defects and that this is partly mediated through myelin plasticity, but the cellular and molecular mechanisms by which this occurs remain poorly understood. One example of the crucial role of myelin plasticity in mental health is the long-term impact of juvenile social isolation (JSI). Children subjected to JSI suffer from dramatic long-term behavioral and cognitive defects that persist after fostering and intervention. Imaging studies indicate that affected children have defects in the myelination of neuronal circuits in the prefrontal cortex (PFC), a brain region implicated in memory, executive function, social interactions, and psychiatric disorders. In prior studies, we found that like in children, mice isolated during their juvenile period also present with long-term defects in social interactions and cognitive function together with altered myelination of PFC neurons. In addition, we have demonstrated that JSI in mice reduces the trophic factor Neuregulin 1 (NRG1) type III in the PFC and that mice with central hypomyelination due to decreased signaling by NRG1 and its ErbB receptors (ErbBRs) have behavioral phenotypes like those produced by JSI. Together, these data suggest that JSI influences PFC myelin plasticity through alterations in NRG1/ErbB signaling, and that the resulting hypomyelination in turn impacts PFC function. However, critical mechanistic aspects of how JSI alters PFC structure and function remain undefined. To fill these gaps in knowledge and to determine if the effects of JSI can be prevented, ameliorated, or reversed by increasing type III NRG1 levels, we propose the following aims. In Aim 1, we will determine the mechanisms by which JSI alters PFC type III NRG1 expression, focusing on epigenetic regulation. Aim 2 will determine the cellular mechanisms by which JSI and hypomyelination alter the function of PFC circuits using patch-clamp recordings combined with laser scanning photo-stimulation (LSPS). In Aim 3, we will determine if the downregulation of NRG1 PFC expression is sufficient to induce the JSI endophenotypes, and if restoration of type III NRG1 expression is sufficient to attenuate, prevent, or rescue the impact of JSI on PFC myelination and function. For the latter aim, we will use new genetically modified mice that allow for cell-specific inducible NRG1 KO or over-expression. The proposed studies, which represent the continuation of a collaboration between labs with complementary expertise, will provide new insights into the mechanisms of myelin plasticity and the interactions between oligodendrocytes and neurons, the mechanisms by which JSI alters neuronal gene expression, the mechanisms regulating the expression of NRG1, a gene involved in psychiatric disorders, and the mechanisms by which myelin disruption alters neuronal function. Elucidation of these mechanisms has the potential to enable intervention...