Mind the gap: Nodes of Ranvier are remodeled by chronic psychosocial stress and neuronal activity

Differential expression of myelin-related genes and changes in myelin thickness have been demonstrated in mice after chronic psychosocial stress, a risk factor for anxiety disorders. To determine whether and how stress affects structural remodeling of nodes of Ranvier, another form of myelin plasticity, we developed a 3D reconstruction analysis of node morphology in C57BL/6NCrl and DBA/2NCrl mice. We identified strain-dependent effects of chronic stress on node morphology, including elongation of paranodes in the medial prefrontal cortex (mPFC) in DBA/2NCrl mice. Furthermore, chronic chemogenetic activation of the ventral hippocampus-to-mPFC pathway resulted in increased risk assessment behavior and shortened paranodes specifically in stimulated axons, providing a direct link between anxiety-like behavior and remodeling of the nodes. Altogether, our data demonstrate genetic regulation of nodal remodeling in stress and suggest an activity-dependent regulation of paranodes in anxiety-related circuits. Nodal remodeling may thus contribute to the aberrant circuit function associated with anxiety disorders.