Neuron-glial interactions shape neural circuit establishment, refinement and function. One of the key neuron-glial interactions takes place between axons and oligodendroglial precursor cells. Interactions between neurons and oligodendrocyte precursor cells (OPCs) promote OPC proliferation, generation of new oligodendrocytes and myelination, shaping myelin development and ongoing adaptive myelin plasticity in the brain. Communication between neurons and OPCs can be broadly divided into paracrine and synaptic mechanisms. Following the Nobel mini-symposium "The Dark Side of the Brain" in late 2019 at the Karolinska Institutet, this mini-review will focus on the bright and dark sides of neuron-glial interactions and discuss paracrine and synaptic interactions between neurons and OPCs and their malignant counterparts.