Alterations in fiber bundles at the striatal Niltubacin interface with the global pallidus are seen by histologic analysis, which may account for this decreased NAA 
signal as NAA is found predominantly in axons and nerve processes. While NAA’s cellular function and consequences of any change in concentrations remain largely un-elucidated, it is abundant, broadly distributed, displays a range of concentrations between different neuronal types and serves as a surrogate marker for neuronal loss and/or neuronal viability. Reduced brain NAA is reported in a wide range of neurological disorders, including Alzheimer’s disease, post-traumatic stress disorder, mesial temporal lobe epilepsy, and schizophrenia. Thus, reduced NAA in the NET KO is consistent with reduced neuronal viability induced by lifelong elevated levels of norepinephrine and/or developmental consequences of disruption of NET. In previous work, we observed that NAA levels in SERT KO and DAT KO mice are not significantly different from those of wildtype littermates. These results highlight the different ramifications of deletion of the different monoamine transporters. There were no morphological alterations in the major structures involved in the reward pathways, although minor expansions and contractions throughout the brain were detected between wildtype littermates and NET KO mice. Similarly, in our other studies with SERT and DAT KO mice, TBM did not reveal differences between the ALK5 Inhibitor II 446859-33-2 knockout mice and wildtype littermates. Thus, structural changes at the resolution employed here do not explain differences in behavioral phenotype: compared to wildtype NET KO mice show enhanced behavioral responses to cocaine, profound hypoalgesia, reduced MPTP toxicity, and less immobility in forced swim test and tail suspension test. Moreover, functional circuitry differences identified via MEMRI are not necessarily reflected in morphology differences identified by TBM at the resolution employed here. MEMRI employs the unique properties of Mn2+ to analyze functional connectivity and patterns of neuronal activity in vivo. Mn2+ preferentially enters active neurons, is transported along microtubules and transmitted across active synapses. Hyperintensity in MEMRI is a consequence of changes in local Mn2+ concentrations determined by at least 4 contributing factors: neuronal uptake at the injection site, packaging and anterograde axonal transport, synaptic release and re-uptake, and intracellular accumulation, likely in endoplasmic reticulum. NET absence is unlikely to affect Mn2+ uptake. The effective delineation of circuitry in the NET KO group confirms satisfactory uptake of Mn2+. Furthermore, by comparing time points within each group, we ensure that any putative differences in uptake between genotypes would not contribute to our conclusions. In the present work, stereotaxic injection of nanoliter amounts of Mn2+ into the mouse prefrontal cortex in NET KO mice and their WT littermates revealed differences in the pattern of functional connectivity from the PFC to distal brain regions as deduced from time dependent manganese induced MRI hyperintensities far from the injection site. The lack of any remarkable pathologic changes around the injection site in histopathologic examination demonstrates that stereotaxic injection of Mn2+.