Manganese-enhanced MRI Research Articles

18. Quantitative Activation-induced Manganese-enhanced MRI for Use in Studying Animal Model of Diseases

18. Quantitative Activation-induced Manganese-enhanced MRI for Use in Studying Animal Model of Diseases

Prenatal Irradiation-Induced Hippocampal Abnormalities in Rats Evaluated Using Manganese-Enhanced MRI.

The aim of this study was to characterize hippocampal abnormalities in rats after prenatal x-ray irradiation using manganese-enhanced MRI (MEMRI). All radiation-exposed rat brains showed a reduced volume with prominent dilatation of lateral ventricles. Moreover, MEMRI-enhanced areas within the hippocampus were reduced in volumes by approximately 25% of controls, although the entire volume of hippocampus was decreased by approximately 50% of controls. MEMRI signals were enhanced strongly in the hilus and granular layer of the dentate gyrus (DG) and the pyramidal layer and infrapyramidal region of the CA3 region, and moderately along the CA1/2 pyramidal cell layer in the control rats. In radiation-exposed rats, MEMRI signals in the CA1/2 regions disappeared due to disrupting their laminar organization, although strong MEMRI signals were sustained in the DG and CA3 regions. Histopathological examinations in radiation-exposed rats revealed disorganizations of the DG granule cell layer and the CA3 pyramidal cell layer with reducing the cell density. The CA1/2 pyramidal cell layer was disrupted by invading ectopic cell mass. Neural cell adhesion molecule (NCAM)-positive fiber bundles were sustained in radiation-exposed rats, although they distributed aberrantly in the suprapyramidal CA3 region with a slight reduction of NCAM staining. Furthermore, glial components consisted largely by astrocytes and minor by microglia were densely distributed in the DG rather than in other hippocampal regions, and their density radiation-exposed rats. In conclusion, MEMRI signal enhancements could delineate different neuronal and/or glial components among hippocampal regions. We characterized microstructures of the deformed hippocampus as well as its macrostructures in a prenatally radiation-exposed rat model using in vivo MEMRI. The present findings provide advantageous information for detecting nondestructively hippocampal deformations in neurodevelopmental disorders.

Oxycodone Exposure: A Magnetic Resonance Imaging Study in Response to Acute and Chronic Oxycodone Treatment in Rats

The present study was designed to use blood-oxygen-level dependent (BOLD) imaging to “fingerprint” the change in activity in response to oxycodone (OXY) in drug naïve rats before and after repeated exposure to OXY. It was hypothesized that repeated exposure to OXY would initiate adaptive changes in brain organization that would be reflected in an altered response to opioid exposure. Male rats exposed to OXY repeatedly showed conditioned place preference, evidence of drug-seeking behavior and putative neuroadaptation. As these studies were done on awake rats we discovered it was not possible to image rats continuously exposed to OXY due to motion artifact judged to be withdrawal while in the scanner. To circumvent this problem manganese-enhanced MRI (MEMRI) was used to map the distributed integrated activity pattern resulting from continuous OXY exposure. Rats were administered OXY (2.5 mg/kg, i.p.) during image acquisition and changes in BOLD signal intensity were recorded and the activation and deactivation of integrated neural circuits involved in olfaction and motivation were identified. Interestingly, the circuitry of the mesencephalic dopaminergic system showed little activity to the first exposure of OXY. In the MEMRI study, rats received OXY treatments (2.5 mg/kg, twice daily) for four consecutive days following intraventricular MnCl2. Under isoflurane anesthesia, T1-weighted images were acquired and subsequently analyzed showing activity in the forebrain limbic system, ventral striatum, accumbens, amygdala and hippocampus. These results show brain activity is markedly different when OXY is presented to drug naïve rats versus rats with prior, repeated exposure to drug.

Manganese-Enhanced T1 Mapping in the Myocardium of Normal and Infarcted Hearts.

Background Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 μmol/kg)) or chelated (mangafodipir (22–44 μmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100–200 μmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson's trichrome (MTC). Results Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30–43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI −14.8 to 17.1 P>0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI −9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI −10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=−0.61, P=0.022). Conclusions MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.

Abstract 077: Captopril-Induced Sustained Reduction in Blood Pressure is Associated With Alterations in Gut-Brain Axis in the Spontaneously Hypertensive Rats

Objective: The anti-hypertensive effect of captopril (CAP) is prolonged even when the treatment is discotinued. Our recent findings indicate the beneficial effect of CAP on hypertension-linked gut pathology. Given the roles of brain and gut/microbiota in hypertension, we hypothesized that prolonged anti-hypertensive effect of CAP is through impacts on the brain-gut axis. Accordingly, we tested if CAP induced alterations in the brain and the gut, and if the changes are preserved in the SHR following CAP withdrawal. Methods: Male SHR and normotensive Wistar Kyoto (WKY) rats were treated with CAP (250mg/kg/day) in water for 4 weeks followed by its withdrawal for 16 weeks (weeks 5-20). Systolic BP was measured by tailcuff at weeks 3, 5, and 9. Fecal microbiota was analyzed at week 4 and week 8. Brain neuronal activity was measured by manganese-enhanced MRI (MEMRI) at weeks 4 and 8. Gut pathology was assessed at week 20. Results: Unweighted principal coordinate analysis showed that CAP treatment significantly altered gut microbial composition, characterized by separate clusters between untreated and 4 weeks CAP-treated SHR. The composition change was preserved 4 weeks post-withdrawal of CAP. Sustained improvement in fibrotic area (untreated: 12.98±0.81% vs week 20: 10.23±0.69%, P=0.036), goblet cell number (untreated: 39±3.57 cells/villi vs week 20: 65±5.29 cells/villi, P=0.0006), and villi length (untreated: 271.4±9.85 μm vs week 20: 388.8±12.29 μm, P<0.0001) was observed at week 20 compared with untreated SHR. MEMRI demonstrated sustained decrease in neuronal activity in autonomic brain regions, with the most pronounced decrease in the posterior pituitary area in SHR treated with CAP (week 4) and withdrawal of CAP (week 8), compared with untreated control (untreated: 1.57±0.11 vs week 4: 1.14±0.074 vs week 8: 1.05±0.14, P=0.0162). In contrast, CAP-treated WKY showed little change in BP, gut pathology or neuronal activity, but distinct changes in gut microbiota. Conclusion: Oral CAP persistently lowered BP, altered gut microbiota, improved gut pathology and reduced posterior pituitary neuronal activity in the SHR even post-withdrawal of CAP, indicating persistent antihypertensive effect of CAP may result from altered brain-gut communication.

Mouse MRI shows brain areas relatively larger in males emerge before those larger in females

Sex differences exist in behaviors, disease and neuropsychiatric disorders. Sexual dimorphisms however, have yet to be studied across the whole brain and across a comprehensive time course of postnatal development. Here, we use manganese-enhanced MRI (MEMRI) to longitudinally image male and female C57BL/6J mice across 9 time points, beginning at postnatal day 3. We recapitulate findings on canonically dimorphic areas, demonstrating MEMRI’s ability to study neuroanatomical sex differences. We discover, upon whole-brain volume correction, that neuroanatomical regions larger in males develop earlier than those larger in females. Groups of areas with shared sexually dimorphic developmental trajectories reflect behavioral and functional networks, and expression of genes involved with sex processes. Also, post-pubertal neuroanatomy is highly individualized, and individualization occurs earlier in males. Our results demonstrate the ability of MEMRI to reveal comprehensive developmental differences between male and female brains, which will improve our understanding of sex-specific predispositions to various neuropsychiatric disorders.

Continuous manganese delivery via osmotic pumps for manganese-enhanced mouse MRI does not impair spatial learning but leads to skin ulceration

Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique in rodent neuroimaging studies. Traditionally, Mn2+ is delivered to animals via a systemic injection; however, this can lead to toxic effects at high doses. Recent studies have shown that subcutaneously implanted mini-osmotic pumps can be used to continuously deliver manganese chloride (MnCl2), and that they produce satisfactory contrast while circumventing many of the toxic side effects. However, neither the time-course of signal enhancement nor the effect of continuous Mn2+ delivery on behaviour, particularly learning and memory, have been well-characterized. Here, we investigated the effect of MnCl2 dose and route of administration on a) spatial learning in the Morris Water Maze and b) tissue signal enhancement in the mouse brain. Even as early as 3 days after pump implantation, infusion of 25–50 mg/kg/day MnCl2 via osmotic pump produced signal enhancement as good as or better than that achieved 24 h after a single 50 mg/kg intraperitoneal injection. Neither route of delivery nor MnCl2 dose adversely affected spatial learning and memory on the water maze. However, especially at higher doses, mice receiving MnCl2 via osmotic pumps developed skin ulceration which limited the imaging window. With these findings, we provide recommendations for route and dose of MnCl2 to use for different study designs.

In Vivo Evaluation of Neuronal Transport in Murine Models of Neurodegeneration Using Manganese-Enhanced MRI.

Manganese-enhanced MRI (MRI) is a technique that allows for a noninvasive in vivo estimation of neuronal transport. It relies on the physicochemical properties of manganese, which is both a calcium analogue being transported along neurons by active transport, and a paramagnetic compound that can be detected on conventional T1-weighted images. Here, we report a multi-session MEMRI protocol that helps establish time-dependent curves relating to neuronal transport along the olfactory tract over several days. The characterization of these curves via unbiased fitting enables us to infer objectively a set of three parameters (the rate of manganese transport from the maximum slope, the peak intensity, and the time to peak intensity). These parameters, measured previously in wild type mice during normal aging, have served as a baseline to demonstrate their significant sensitivity to pathogenic processes associated with Tau pathology. Importantly, the evaluation of these three parameters and their use as indicators can be extended to monitor any normal and pathogenic processes where neuronal transport is altered. This approach can be applied to characterize and quantify the effect of any neurological disease conditions on neuronal transport in animal models, together with the efficacy of potential therapies.

Mn2+ dynamics in manganese-enhanced MRI (MEMRI): Cav1.2 channel-mediated uptake and preferential accumulation in projection terminals

Manganese-enhanced magnetic resonance imaging (MEMRI) exploits the biophysical similarity of Ca2+ and Mn2+ to map the brain's activity in vivo. However, to what extent different Ca2+ channels contribute to the enhanced signal that MEMRI provides and how Mn2+ dynamics influence Mn2+ brain accumulation after systemic administration of MnCl2 are not yet fully understood. Here, we demonstrate that mice lacking the L-type Ca2+ channel 1.2 (Cav1.2) in the CNS show approximately 50% less increase in MEMRI contrast after repeated systemic MnCl2 injections, as compared to control mice. In contrast, genetic deletion of L-type Ca2+ channel 1.3 (Cav1.3) did not reduce signal. Brain structure- or cell type-specific deletion of Cav1.2 in combination with voxel-wise MEMRI analysis revealed a preferential accumulation of Mn2+ in projection terminals, which was confirmed by local MnCl2 administration to defined brain areas.Taken together, we provide unequivocal evidence that Cav1.2 represents an important channel for neuronal Mn2+ influx after systemic injections. We also show that after neuronal uptake, Mn2+ preferentially accumulates in projection terminals.

A rapid T1 mapping method for assessment of murine kidney viability using dynamic manganese-enhanced magnetic resonance imaging.

Dynamic manganese-enhanced MRI (MEMRI) allows assessment of tissue viability by tracing manganese uptake. We aimed to develop a rapid T1 mapping method for dynamic MEMRI to facilitate assessments of murine kidney viability. A multi-slice saturation recovery fast spin echo (MSRFSE) was developed, validated, and subsequently applied in dynamic MEMRI at 16.4T on ischemic mouse kidneys after 4 weeks of unilateral renal artery stenosis (RAS). Baseline T1 values and post-contrast R1 (1/T1 ) changes were measured in cortex (CO), outer (OSOM), inner (ISOM) strips of outer medulla, and inner medulla (IM). Validation studies showed strong agreement between MSRFSE and an established saturation recovery Look-Locker method. Baseline T1 (s) increased in the stenotic kidney CO (2.10 [1.95-2.56] vs. 1.88 [1.81-2.00], P = 0.0317) and OSOM (2.17 [2.05-2.33] vs. 1.96 [1.87-2.00], P = 0.0075) but remained unchanged in ISOM and IM. This method allowed a temporal resolution of 1.43 min in dynamic MEMRI. Mn2+ uptake and retention decreased in stenotic kidneys, particularly in the OSOM (ΔR1 : 0.48 [0.38-0.56] vs. 0.64 [0.61-0.69] s-1 , P < 0.0001). Dynamic MEMRI by MSRFSE detected decreased cellular viability and discerned the regional responses to RAS. This technique may provide a valuable tool for noninvasive evaluation of renal viability. Magn Reson Med 80:190-199, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Manganese-enhanced MRI for the detection of metastatic potential in colorectal cancer

BackgroundTo study manganese superoxide dismutase (MnSOD) expression, manganese-enhanced magnetic resonance imaging (MEMRI) appearance and its relation to metastatic potential in colorectal cancer (CRC).MethodsCRC cells SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and their normal counterpart CCD841 CoN were chosen, based on differential aggressiveness, to undergo Western blot analysis for assessment of MnSOD expression, reported as proportion of readings to internal reference (glyceraldehyde-3-phosphate-dehydrogenase). Based on the results of the invasion assay, HCT15, DLD-1, LoVo and SW620 cells and corresponding xenografts underwent MEMRI. The differences of average T1-value shortening were compared.ResultsMnSOD expression in SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and CCD841 CoN cells (0.255 ± 0.018 (mean ± standard deviation), 0.289 ± 0.028, 0.438 ± 0.028, 0.337 ± 0.025, 0.777 ± 0.031, 1.045 ± 0.038, 0.163 ± 0.035 and 0.185 ± 0.038, respectively) was not correlated with Invasion Index (22.6 ± 0.7, 17.0 ± 0.6, 20.9 ± 0.6, 9.7 ± 0.4, 7.5 ± 0.3, 8.3 ± 0.2, 12.6 ± 0.5 and 0) (r = − 0.204, p = 0.627). In highly aggressive cells (SW620, LoVo), T1 shortening (289.33 ± 0.57, 268.45 ± 6.87 ms, respectively) was greater than that in lower counterparts (148.68 ± 3.99 ms in DLD-1, 128.60 ± 1.96 in HCT15) (p < 0.001). Both 5- and 10-mm group SW620 and/or LoVo tumours showed greater T1 shortening (≥600 ms) than DLD-1 and HCT15 (≤350 ms) (p < 0.001, p = 0.005, p = 0.010).ConclusionsMEMRI has the potential to noninvasively distinguish different metastatic potential CRCs. However, the MnSOD expression is not correlated to malignant potential in CRC cells.

BOLD-fMRI in the mouse auditory pathway

The auditory pathway is widely distributed throughout the brain, and is perhaps one of the most interesting networks in the context of neuroplasticity. Accurate mapping of neural activity in the entire pathway, preferably noninvasively, and with high resolution, could be instrumental for understanding such longitudinal processes. Functional magnetic resonance imaging (fMRI) has clear advantages for such characterizations, as it is noninvasive, provides relatively high spatial resolution and lends itself for repetitive studies, albeit relying on an indirect neurovascular coupling to deliver its information. Indeed, fMRI has been previously used to characterize the auditory pathway in humans and in rats. In the mouse, however, the auditory pathway has insofar only been mapped using manganese-enhanced MRI. Here, we describe a novel setup specifically designed for high-resolution mapping of the mouse auditory pathway using high-field fMRI. Robust and consistent Blood-Oxygenation-Level-Dependent (BOLD) responses were documented along nearly the entire auditory pathway, from the cochlear nucleus (CN), through the superior olivary complex (SOC), nuclei of the lateral lemniscus (LL), inferior colliculus (IC) and the medial geniculate body (MGB). By contrast, clear BOLD responses were not observed in auditory cortex (AC) in this study. Diverse BOLD latencies were mapped ROI- and pixel-wise using coherence analysis, evidencing different averaged BOLD time courses in different auditory centers. Some degree of tonotopy was identified in the IC, SOC, and MGB in the pooled dataset though it could not be assessed per subject due to a lack of statistical power. Given the importance of the mouse model in plasticity studies, animal models, and optogenetics, and fMRI's potential to map dynamic responses to specific cues, this first fMRI study of the mouse auditory pathway paves the way for future longitudinal studies studying brain-wide auditory-related activity in vivo.

184 Sirolimus interferes with the calcium influx to reduce the neuropathic pain in Fabry disease

The neuropathic pain is the key feature of Fabry disease and has a severe impact on the quality of life. However, as to ineffective or renal involvement, only anticonvulsants can be used, even it also shows big side effect. Calcium ions play a fundamental role in several biological processes. As the marker of Fabry disease, globotriaosylsphingoshine enhances calcium currents in dorsal root ganglia neurons. Moreover, evidences have accumulated for the efficacy of sirolimus in blocking calcium influx. Here we investigate the efficacy of sirolimus on neuropathic pain in Fabry disease. First, plantar test was investigated. Sirolimus recovered the Fabry mice thermal sensitivity to normal. However, it shows opposite function against wild type mice. 1% voltaren only works on wild type but not the Fabry mice. Second, to clarify the calcium ions currents in vivo, manganese-enhanced MRI (MEMRI) was performed. With heat stimulation, there are much more accumulated manganese ions in Fabry mice brain. 0.2% sirolimus reduced the manganese ions’ concentration in Fabry but increased it in wild type mice. Third, α-gal A CRISPR/Cas9 KO plasmid and HDR plasmid were co-transfected into SK-N-MC, U-87 MG, F11 and normal human dermal fibroblasts (NHDF). Then calcium influx was determined by Fura-2. Only knockout neurons, SK-M-MC and F11 but not U-87 MG and NHDF increased calcium influx in response to glutamate or capsaicin. Sirolimus totally inhibited the calcium flux into SK-N-MC but F11, U-87 MG and NHDF. At last, the western blot and quantity real-time PCR were performed. Sirolimus fulfilled the similar efficacy to voltaren on nerve growth factor (NGF). However, it revealed different function against brain-derived neurotrophic factor (BDNF). It increased the activity of cAMP response element binding protein (CREB) to enhance BDNF transcription and blocked CaMKIIα to release the BDNF to the serum. Combining all results, sirolimus might be a useful alternative for clinical neuropathic pain management in Fabry disease.

In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

Investigation of spinal nerve ligation-mediated functional activation of the rat brain using manganese-enhanced MRI.

To provide clear information on the cerebral regions according to peripheral neuropathy, the functional activation was investigated using manganese-enhanced magnetic resonance imaging (MEMRI). L5-spinal nerve ligation (SNL) was applied to the rats to induce neuropathic pain. Mechanical allodynia and thermal hyperalgesia were measured to confirm neuropathic pain induction following before and after gabapentin (GBP) treatment. The cerebral regions were investigated using a 4.7T MRI system in the sham, SNL, and GBP-treated SNL rats. Neuropathic pain was severely induced by SNL on the postoperative day 14, excepting the sham group. While MEMRI indicated many activation regions in the brain of SNL rats before GBP treatment, the activities were chronologically attenuated after GBP treatment. The brain regions relating SNL-induced neuropathic pain were as follows: the posterior association area of the parietal region, superior colliculus, inferior colliculus, primary somatosensory area, cingulate cortex, and cingulum bundle. SNL induced- neuropathic pain is transmitted to the primary somatosensory area and parietal region through the cingulum bundle and limbic system. These findings would be helpful for the understanding of neuropathic pain-associated process and be an accurate target for a relief of neuropathic pain.

Blast-Induced Tinnitus and Elevated Central Auditory and Limbic Activity in Rats: A Manganese-Enhanced MRI and Behavioral Study

Blast-induced tinitus is the number one service-connected disability that currently affects military personnel and veterans. To elucidate its underlying mechanisms, we subjected 13 Sprague Dawley adult rats to unilateral 14 psi blast exposure to induce tinnitus and measured auditory and limbic brain activity using manganese-enhanced MRI (MEMRI). Tinnitus was evaluated with a gap detection acoustic startle reflex paradigm, while hearing status was assessed with prepulse inhibition (PPI) and auditory brainstem responses (ABRs). Both anxiety and cognitive functioning were assessed using elevated plus maze and Morris water maze, respectively. Five weeks after blast exposure, 8 of the 13 blasted rats exhibited chronic tinnitus. While acoustic PPI remained intact and ABR thresholds recovered, the ABR wave P1-N1 amplitude reduction persisted in all blast-exposed rats. No differences in spatial cognition were observed, but blasted rats as a whole exhibited increased anxiety. MEMRI data revealed a bilateral increase in activity along the auditory pathway and in certain limbic regions of rats with tinnitus compared to age-matched controls. Taken together, our data suggest that while blast-induced tinnitus may play a role in auditory and limbic hyperactivity, the non-auditory effects of blast and potential traumatic brain injury may also exert an effect.

TAU OLIGOMERS MEDIATE RIBOSOMAL DYSFUNCTION AT THE SYNAPSE

Tau is known to interact with ribosomes both under normal and Alzheimer's disease conditions. We have shown that oligomeric tau, a conformer associated with tau toxicity, impairs ribosomal activity and attenuates nascent protein translation. We hypothesize the tau mediated impairment of ribosome function is a key process in the pathogenesis of Alzheimer's disease and other tauopathies. The impact of tau-mediated impairment of ribosomal function on synaptic proteins was assessed by treating primary neurons with tau oligomers and collecting synaptic fractions. These fractions were analyzed with surface sensing of translation (SUnSET) to determine ribosomal function at the synapse. Changes in the levels and types of mRNA and protein were also determined. The in vitro data was expanded by examining protein translation in rTg4510 tau transgenic mice using an innovative approach of adapting SUnSET in vivo. Protein synthesis as measured by immunohistochemistry and biochemical analysis of synaptosome fractions. Broad neuronal function measures were performed using manganese-enhanced MRI with R1 mapping, a novel MRI approach developed in our laboratory. Cognitive status was evaluated using a battery of behavioral tests. Tau oligomers impaired translation of key synaptic proteins both in primary neurons and rTg4510 mice. Further, tau-mediated impaired protein synthesis in rTg4510 mice was readily detectable by SUnSET. Finally, we identified rescue of broad neuronal function and cognition in tau transgenic when tau transgenic mice were treated with compounds that uncouple the tau-ribosome association. These data suggest that a key pathway contributing to cognitive deficits characteristic of tauopathies such as AD may be tau-mediated impairment of synaptic protein synthesis. Future efforts will focus on identifying and validating therapeutic strategies to rescue dysfunctional synaptic protein synthesis.

Automated Computational Processing of 3-D MR Images of Mouse Brain for Phenotyping of Living Animals.

Magnetic resonance (MR) imaging provides a method to obtain anatomical information from the brain in vivo that is not typically available by optical imaging because of this organ's opacity. MR is nondestructive and obtains deep tissue contrast with 100-µm3 voxel resolution or better. Manganese-enhanced MRI (MEMRI) may be used to observe axonal transport and localized neural activity in the living rodent and avian brain. Such enhancement enables researchers to investigate differences in functional circuitry or neuronal activity in images of brains of different animals. Moreover, once MR images of a number of animals are aligned into a single matrix, statistical analysis can be done comparing MR intensities between different multi-animal cohorts comprising individuals from different mouse strains or different transgenic animals, or at different time points after an experimental manipulation. Although preprocessing steps for such comparisons (including skull stripping and alignment) are automated for human imaging, no such automated processing has previously been readily available for mouse or other widely used experimental animals, and most investigators use in-house custom processing. This protocol describes a stepwise method to perform such preprocessing for mouse. © 2017 by John Wiley & Sons, Inc.

158 Quantifying manganese-calcium interaction for optimal cardiac manganese enhanced mri

IntroductionInformation on myocardial viability is important for the management of ischaemic cardiomyopathy patient. Difficulties in assessing viability arise because necrotic tissue and viable myocardium overlap at the infarct border zone....

Transcranial manganese delivery for neuronal tract tracing using MEMRI

There has been a growing interest in the use of manganese-enhanced MRI (MEMRI) for neuronal tract tracing in mammals, especially in rodents. For this MEMRI application, manganese solutions are usually directly injected into specific brain regions. Recently it was reported that manganese ions can diffuse through intact rat skull. Here the local manganese concentrations in the brain tissue after transcranial manganese application were quantified and the effectiveness of tracing from the area under the skull where delivery occurred was determined. It was established that transcranially applied manganese yields brain tissue enhancement dependent on the location of application on the skull and that manganese that enters the brain transcranially can trace to deeper brain areas.