MEMRI in normal animals provides novel information relevant to anatomical, integrative, and functional assessments of neural connectivity. Significant works have focused on the use of MEMRI for studies of pathobiology of neurodegenerative diseases. However, the cellular mechanisms underlying the MEMRI signal changes caused by neuropathology are still controversial. We have demonstrated that neurons stimulated by astrocytic activation represent a significant cellular response to induce MEMRI signal enhancement in brain inflammation¹. With this in mind, MEMRI was successfully used to detect HIV-1 infection induced inflammation in humanized mice². The goal of this study was to delineate cellular mechanisms of MEMRI signals as neuronal injury progresses. Neuronal injury was generated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) injection in mice as a model of Parkinson’s disease. Neuronal loss and gliosis in this mouse model is well-characterized^3,4.MPTP (18 mg/kg x 4 doses at 2 hrs/dose, n = 6) or PBS (10 ml/kg, n = 5) was injected into mice via i.p. route. MnCl₂ (60 mg/kg) was injected i.p. 4 hours after MPTP/PBS. The 2^nd MnCl₂ injection was carried out 24 hours after MPTP/PBS. MRI was performed 48 hours after MPTP/PBS on a 7T/21 cm MRI scanner (Bruker, Billerica, MA). Mice were scanned using T₁-wt MRI (3D FLASH, TR = 20 ms, flip angle = 20^o). The T₁-wt images were then registered to a MEMRI-based rat brain atlas and compared by t-tests for regional MRI signal enhancement between PBS controls and MPTP injected mice. After MRI, animals were euthanized and brains recovered for immunohistological validation. Thirty μm frozen sections were labeled with rabbit polyclonal antibody for tyrosine hydroxylase (TH+). Images were captured with 10× objective using Nuance EX multispectral imaging system fixed to a Nikon Eclipse E800.Fig 1 shows the averaged MEMRI enhancement in MPTP mice (Fig 1A) and PBS controls (Fig 1B). Signal intensities of substantia nigra (SN) and hypothalamus (HY) were lower in MPTP mice compared to controls (P<0.05, Fig 2A). In addition, signal intensities of motorsensory cortex (MS-Ctx), and striatum (STR) were higher in MPTP mice compared to controls (P<0.05, Fig 2B). Dopaminergic (DA) neuron loss was observed in MPTP mice (Fig 3).After MPTP intoxication, significant DA neuron loss occurs within the SN and striatum and the rate of neurodegeneration reaches maximum at 2 days post-injection³. Gliosis is also significant by day 2⁴. Our previous study² demonstrated MEMRI enhancement correlates with astrocyte activation. In another study³, we determined that, gliosis and neuronal damage occur simultaneously, but offset the effects of neuronal activation and astrocyte activation. The combined pathologic effects determine MEMRI results. This study indicated at 2 days after MPTP injection, the effect of neuronal loss outweighed gliosis producing decreased MEMRI signal intensity within the SN and HY. Immunohistological analysis confirmed the neuronal loss in SN. The signal enhancement on MS-Ctx and STR suggested elevated glial activation. We are working on immunohistology to confirm the finding. These results confirm the ability of MEMRI to detect frank neurodegeneration and areas of neuroinflammation, which is proven by our previous studies^1,2 , as well as documenting the effects of MPTP on HY, an unexpected finding.