This symposium will discuss a) novel mechanisms of CNS and peripheral metabolic function (insulin resistance, the mitochondrial pathway of epigenetic regulation of neuroplasticity, neuropeptides) in cross-species models; b) the crosstalk between glial cells and neurons in the regulation of neuroplasticity and c) the need for integrated system-level strategies to identify and more effectively treat biologically based subtypes of depressive disorders and block the progression to dementia. New data of brain-enriched exosomes will also be presented as a new frontier to study in-vivo CNS molecular mechanisms in humans. Pierre Magistretti will present new data on the role of neuron-glia metabolic coupling in neuronal plasticity and neuropsychiatric disorders pointing to a novel action of L-lactate as a signaling molecule in addition to its role as an energy substrate. Carla Nasca (presenter) will present new data on the role of exosomes in psychiatric disorders and the emerging role of mitochondria as regulators of epigenetic programming of neuroplasticity in depressive disorders and rodent models. Aleksander Mathe will discuss the impact of targeting neuropeptide Y pathways in depressive disorders and post-traumatic stress disorder and present both preclinical and clinical data. Natalie Rasgon (chair and presenter) will describe conceptual model of the panel as a unique translational platform for studies of metabolic phenotypes in the progression from depressive disorders to dementia.