Abstract Text: Traumatic brain injury (TBI) is a serious public health problem and a leading cause of death in children and young adults. It also contributes to a substantial number of cases of permanent disability. As lipids make up over 63% of the brain’s mass and play a key role in both membrane structure and cell signaling, their profile is of particular interest. We studied a mouse model of Blast Induced TBI (bTBI) and a rat model of Controlled Cortical Impact (CCI) focusing on brain tissue lipids profile changes over time using mass spectrometry imaging (MSI). Its technical accuracy and reproducibility allowed us to show drastic changes in brain lipids distribution and that the lipids biochemical pathways involved differs in bTBI and CCI. In bTBI the explosive detonations generate atmospheric pressure changes producing nonpenetrating blast induced “mild” TBI. The variability is generated by Latency between blast and tissue sampling and distance from the blast, resulting in a huge increase of the ganglioside GM2 in the hippocampus, hypothalamus, and thalamus, after a single blast exposure. In CCI adult male rats received one strike and were euthanized 3 days post trauma. Ceramides (cer) distribution and concentration were evaluated in both animals with and without treatment using a dynorphin binding peptide. Brain MS images showed a marked increase in cer in CCI animals compared to control as well as significant reduction in cer in the CCI peptide treated animal group compared to the untreated group, demonstrating the therapeutic effect of a peptide that binds dynorphin, a mediator of stress responses. Diffuse axonal injury was only found in the CCI animals and was absent in the peptide treated group. These results shed light on the extent of biochemical and structural changes in the brain after TBI and could help evaluate the efficacy of treatments. A single dose of the dynorphin binding peptide significantly attenuated CCI-induced upregulation of all cer species.