The clinical manifestations, such as cognitive deficits and post-traumatic stress or affective disorders have correlated with abnormalities that are persistent in white matter tracts following blast traumatic brain injury (bTBI) [1]. To date, rats have been the most widely used species to study bTBI in a pre-clinical setting; however, the use of mice is more practical due to the low-cost, high-throughput, and availability of transgenic models [2]. The effects of blast exposure at different intensities has not been characterized in the mouse brain. Here, MRI including conventional (T2 and T2*), DTI and advanced CEST pulse sequences were used to assess acute and chronic WM changes following mbTBI. Concurrent behavioral and neuropathological abnormalities were evaluated with the goal of establishing baselines for therapeutic interventions.For acute studies, male BALB/c (WT) (n=8/ group) were subjected to single or 2-3 closely coupled repeated blast overpressure (BOP) exposures at 17, 20, or 23 psi peak positive pressures and 8-9 msec positive phase durations. T2 and T2* images were acquired one day following BOP exposure. For chronic studies, male WT and rag-/- (immunodeficient) mice were exposed (n=6/group) to 17*2 psi BOP; controls underwent the same procedure, except for BOP. A Bruker BioSpec 11.7 T MR scanner, equipped with a phase-array coil and one 72 mm volume coil (Bruker) was used for DTI-EPI and CEST imaging. DTI was performed with 30 directions, TE= 24.5ms, TR = 9s, b = 1500 s/mm2, and slice thickness =0.5 mm at day 1, day 7, and at 1-4-month time points. Chemical exchange saturation transfer (CEST) was performed at a saturation offset of -8 ppm to 8 ppm (0.4 ppm increment) using a 2 µT, three-second-long continuous wave (CW) saturation RF pulse, with readout consisting of a RARE factor=20, TR= 6 s, TE = 4 s, slice thickness =1 mm. All scans had FOV= 15mm×15mm, with a 128×128 acquisition matrix. Oligodendrocyte precursors in selected regions were quantified with Olig2 antibody immunohistochemistry. Learning and memory were assessed with a novel object recognition task.T2* images obtained one day following injury revealed no intracerebral hemorrhage; however, decreased ventricular volumes were observed in all bTBI groups (Figure 1). Time dependent changes in AD and FA diffusion are shown in Fig 3. At one day, WT mice demonstrated a decrease in AD in the OT, IC and Fi. The number of Olig2+ cells 4 days following BOP was reduced, with the most pronounced reduction observed in the corpus callosum (CC) and IC (Figure 2). At one week, no changes were observed in AD and FA in any of the regions. AD increased in IC and OT at 1-3 months and in Fi at 1- and 2-months, and a persisting increase was observed only in the CC at four months. FA was reduced in Fi at one day and at four months. FA was increased in CC at 1 and 2 months and in IC at 3 months, with no FA changes observed in OT. Immunodeficient mice evaluated at one day had no changes in AD however FA was decreased in the IC; 7 days following BOP, a significant increase in AD was observed in the IC and Fi, while an increase was observed only in the Fi. CEST demonstrated abnormalities in hippocampal regions at 1ppm at one day (Figure 4). Significant impairment in learning and memory was observed through 1-4 months of chronic stage analysis in WT mice (Figure 5). Our murine experiments successfully demonstrated specific neuroimaging, behavioral and neuropathological changes associated with mbTBI, suggesting a clinically relevant translational model. The reduction of ventricle volume observed in the acute setting is an important observation that could be related to edema. This could be associated with increased intracranial pressure and is consistent with previous rat models of mbTBI. In line with clinical observations, we found no focal brain injury in any of the pressure groups. The increases in FA and AD in WT and Rag2 mice have been noted in human DTI studies of mbTBI [3], however their neurobiological basis is unknown. Thus post mortem studies are warranted to understand the cellular and molecular basis for DTI and CEST MRI changes. Collectively, these results present a methodological framework for mbTBI research in mice, opening the way for genetically modified strains to further evaluate the neuropathogenesis of blast and identify therapeutic targets.An experimental paradigm of mbTBI has been established in WT and immunodeficient mice. Results indicate distributed WM abnormalities and associated neuropathological and behavioral abnormalities, suggesting a clinically relevant model system.