Lipidomic remodeling of the brain and muscle in a zebrafish model of depression

Major depressive disorder (MDD) is a highly prevalent and disabling psychiatric condition, increasingly recognized as a systemic disorder involving central and peripheral pathophysiological alterations. In this study, we used a multidimensional approach using zebrafish (Danio rerio) exposed to an unpredictable chronic stress (UCS) protocol as a model of MDD, to unravel the plasticity of the lipidome in this mental disorder. Behavioral analyses revealed a reduction in sociability and locomotor activity in stressed animals, accompanied by significantly elevated cortisol levels. Fatty acid profiling demonstrated a decrease in n-3 (omega-3) polyunsaturated fatty acids (PUFA) and an increase in n-3 (omega-6) PUFA, which was more evident in the brain than in the muscle. After UCS, lipidomic analysis revealed a remodeling of the brain lipid profile, including the modulation of several phospholipid and sphingolipid species that may impact cell membrane properties and cause neuronal dysfunction. Some of these species have been previously correlated with neuroinflammation and impaired neurotransmission. An increase in plasmalogen phospholipids, well-known endogenous oxidant signaling molecules, suggests a dysregulation of the redox state. In muscle, lipidomic alterations were characterized by elevated levels of acylcarnitines, indicative of altered mitochondrial energy metabolism, and ceramides, well-known pro-inflammatory and pro-apoptotic molecules. This study highlights the relevance of lipidomic plasticity in the pathophysiology of MDD, associated with behavioral effects similar to MDD symptoms.