[ { "id": "authors:dmpzh-6sr57", "collection": "authors", "collection_id": "dmpzh-6sr57", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200515-084920122", "type": "article", "title": "Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI", "author": [ { "family_name": "Uselman", "given_name": "Taylor W.", "clpid": "Uselman-T-W" }, { "family_name": "Barto", "given_name": "Danial R.", "clpid": "Barto-D-R" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" }, { "family_name": "Bearer", "given_name": "Elaine L.", "orcid": "0000-0002-8390-8529", "clpid": "Bearer-E-L" } ], "abstract": "Life threatening fear after a single exposure evolves in a subset of vulnerable individuals to anxiety, which may persist for their lifetime. Yet neither the whole brain's response to innate acute fear nor how brain activity evolves over time is known. Sustained neuronal activity may be a factor in the development of a persistent fear response. We couple two experimental protocols to provoke acute fear leading to prolonged fear: Predator stress (PS), a naturalistic approach to induce fear in rodents; and Serotonin transporter knockout mouse (SERT-KO) that responds to PS with sustained defensive behavior. Behavior was monitored before, during and at short and long times after PS in wild type (WT) and SERT-KO mice. Both genotypes responded to PS with defensive behavior. SERT-KO retained defensive behavior for 23 days, while WT mice returned to baseline exploratory behavior by 9 days. Thus, differences in neural activity between WT and SERT-KO 9 days after PS identifies neural correlates of persistent defensive behavior, in mice. We used longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to identify brain-wide neural activity associated with different behaviors. Mn\u00b2\u207a accumulation in active neurons occurs in awake, behaving mice and is retrospectively imaged. Following the same two cohorts of mice, WT and SERT-KO, longitudinally allowed unbiased quantitative comparisons of brain-wide activity by statistical parametric mapping (SPM). During natural behavior in WT, only low levels of activity-induced Mn\u00b2\u207a-accumulation were detected, while much more accumulation appeared immediately after PS in both WT and SERT-KO, and evolved at 9 days to a new activity pattern (p\u202f<\u202f0.0001, uncorr., T\u202f=\u202f5.4). Patterns of accumulation differed between genotypes, with more regions of the brain and larger volumes within regions involved in SERT-KO than WT. A new computational segmentation analysis, using our InVivo Atlas based on a manganese-enhanced MR image of a living mouse, revealed dynamic changes in the volume of significantly enhanced voxels within each segment that differed between genotypes across 45 of 87 segmented regions. At Day 9 after PS, the striatum and ventral pallidum were active in both genotypes but more so in the SERT-KO. SERT-KO also displayed sustained or increased volume of Mn\u00b2\u207a accumulations between Post-Fear and Day 9 in eight segments where activity was decreased or silenced in WT. C-fos staining, an alternative neural activity marker, of brains from the same mice fixed at conclusion of imaging sessions confirmed that MEMRI detected active neurons. Intensity measurements in 12 regions of interest (ROIs) supported the SPM results. Between group comparisons by SPM and of ROI measurements identified specific regions differing between time points and genotypes. We report brain-wide activity in response to a single exposure of acute fear, and, for the first time, its evolution to new activity patterns over time in individuals vulnerable to persistent fear. Our results show multiple regions with dynamic changes in neural activity and that the balance of activity between segments is disordered in the SERT-KO. Thus, longitudinal MEMRI represents a powerful approach to discover how brain-wide activity evolves from the natural state either after an experience or during a disease process.", "doi": "10.1016/j.neuroimage.2020.116975", "pmcid": "PMC7805483", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2020-11-15", "volume": "222", "pages": "Art. No. 116975" }, { "id": "authors:r4ynj-mh664", "collection": "authors", "collection_id": "r4ynj-mh664", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191223-160903062", "type": "article", "title": "Decoupling the Effects of the Amyloid Precursor Protein From Amyloid-\u03b2 Plaques on Axonal Transport Dynamics in the Living Brain", "author": [ { "family_name": "Medina", "given_name": "Christopher S.", "clpid": "Medina-C-S" }, { "family_name": "Uselman", "given_name": "Taylor W.", "clpid": "Uselman-T-W" }, { "family_name": "Barto", "given_name": "Daniel R.", "clpid": "Barto-D-R" }, { "family_name": "Ch\u00e1ves", "given_name": "Frances", "clpid": "Ch\u00e1ves-F" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" } ], "abstract": "Amyloid precursor protein (APP) is the precursor to A\u03b2 plaques. The cytoplasmic domain of APP mediates attachment of vesicles to molecular motors for axonal transport. In APP-KO mice, transport of Mn\u00b2\u207a is decreased. In old transgenic mice expressing mutated human (APP^(SwInd)) linked to Familial Alzheimer's Disease, with both expression of APP^(SwInd) and plaques, the rate and destination of Mn\u00b2\u207a axonal transport is altered, as detected by time-lapse manganese-enhanced magnetic resonance imaging (MEMRI) of the brain in living mice. To determine the relative contribution of expression of APP^(SwInd) versus plaque on transport dynamics, we developed a Tet-off system to decouple expression of APP^(SwInd) from plaque, and then studied hippocampal to forebrain transport by MEMRI. Three groups of mice were compared to wild-type (WT): Mice with plaque and APP^(SwInd) expression; mice with plaque but suppression of APP^(SwInd) expression; and mice with APP^(SwInd) suppressed from mating until 2 weeks before imaging with no plaque. MR images were captured before at successive time points after stereotactic injection of Mn\u00b2\u207a (3\u20135 nL) into CA3 of the hippocampus. Mice were returned to their home cage between imaging sessions so that transport would occur in the awake freely moving animal. Images of multiple mice from the three groups (suppressed or expressed) together with C57/B6J WT were aligned and processed with our automated computational pipeline, and voxel-wise statistical parametric mapping (SPM) performed. At the conclusion of MR imaging, brains were harvested for biochemistry or histopathology. Paired T-tests within-group between time points (p = 0.01 FDR corrected) support the impression that both plaque alone and APP^(SwInd) expression alone alter transport rates and destination of Mn\u00b2\u207a accumulation. Expression of APP^(SwInd) in the absence of plaque or detectable A\u03b2 also resulted in transport defects as well as pathology of hippocampus and medial septum, suggesting two sources of pathology occur in familial Alzheimer's disease, from toxic mutant protein as well as plaque. Alternatively mice with plaque without APP^(SwInd) expression resemble the human condition of sporadic Alzheimer's, and had better transport. Thus, these mice with APP^(SwInd) expression suppressed after plaque formation will be most useful in preclinical trials.", "doi": "10.3389/fncel.2019.00501", "pmcid": "PMC6901799", "issn": "1662-5102", "publisher": "Frontiers Research Foundation", "publication": "Frontiers in Cellular Neuroscience", "publication_date": "2019-12-03", "volume": "13", "pages": "Art. No. 501" }, { "id": "authors:czxg7-kdh05", "collection": "authors", "collection_id": "czxg7-kdh05", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20180628-144201687", "type": "article", "title": "Alterations of functional circuitry in aging brain and the impact of mutated APP expression", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Manifold-Wheeler", "given_name": "Brett C.", "clpid": "Manifold-Wheeler-B-C" }, { "family_name": "Medina", "given_name": "Christopher S.", "clpid": "Medina-C-S" }, { "family_name": "Gonzales", "given_name": "Aaron", "clpid": "Gonzales-A" }, { "family_name": "Ch\u00e1ves", "given_name": "Frances", "clpid": "Ch\u00e1ves-F" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Alzheimer's disease (AD) is a disease of aging that results in cognitive impairment, dementia and death. Pathognomonic features of AD are amyloid plaques composed of proteolytic fragments of the amyloid precursor protein (APP) and neurofibrillary tangles composed of hyperphosphorylated tau protein. One type of familial Alzheimer's disease (FAD) occurs when mutant forms of APP are inherited. Both APP and tau are components of the microtubule-based axonal transport system, which prompts the hypothesis that axonal transport is disrupted in AD, and that such disruption impacts cognitive function. Transgenic mice expressing mutated forms of APP provide preclinical experimental systems to study AD. Here we perform manganese-enhanced magnetic resonance imaging (MEMRI) to study transport from hippocampus to forebrain in four cohorts of living mice: young and old wild-type and transgenic mice expressing a mutant APP with both Swedish and Indiana mutations (APPSwInd). We find that transport is decreased in normal aging and further altered in aged APPSwInd plaque-bearing mice. These findings support the hypothesis that transport deficits are a component of AD pathology and thus may contribute to cognitive deficits.", "doi": "10.1016/j.neurobiolaging.2018.06.018", "issn": "0197-4580", "publisher": "Elsevier", "publication": "Neurobiology of Aging", "publication_date": "2018-10", "volume": "70", "pages": "276-290" }, { "id": "authors:k2t3w-xr183", "collection": "authors", "collection_id": "k2t3w-xr183", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20161024-101809831", "type": "article", "title": "Hippocampal to basal forebrain transport of Mn^(2+) is impaired by deletion of KLC1, a subunit of the conventional kinesin microtubule-based motor", "author": [ { "family_name": "Medina", "given_name": "Christopher S.", "clpid": "Medina-C-S" }, { "family_name": "Biris", "given_name": "Octavian", "clpid": "Biris-O" }, { "family_name": "Falzone", "given_name": "Tomas L.", "clpid": "Falzone-T-L" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Zimmerman", "given_name": "Amber J.", "clpid": "Zimmerman-A-J" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" } ], "abstract": "Microtubule-based motors carry cargo back and forth between the synaptic region and the cell body. Defects in axonal transport result in peripheral neuropathies, some of which are caused by mutations in KIF5A, a gene encoding one of the heavy chain isoforms of conventional kinesin-1. Some mutations in KIF5A also cause severe central nervous system defects in humans. While transport dynamics in the peripheral nervous system have been well characterized experimentally, transport in the central nervous system is less experimentally accessible and until now not well described. Here we apply manganese-enhanced magnetic resonance (MEMRI) to study transport dynamics within the central nervous system, focusing on the hippocampal-forebrain circuit, and comparing kinesin-1 light chain 1 knock-out (KLC-KO) mice with age-matched wild-type littermates. We injected Mn^(2+) into CA3 of the posterior hippocampus and imaged axonal transport in vivo by capturing whole-brain 3D magnetic resonance images (MRI) in living mice at discrete time-points after injection. Precise placement of the injection site was monitored in both MR images and in histologic sections. Mn^(2+)-induced intensity progressed along fiber tracts (fimbria and fornix) in both genotypes to the medial septal nuclei (MSN), correlating in location with the traditional histologic tract tracer, rhodamine dextran. Pairwise statistical parametric mapping (SPM) comparing intensities at successive time-points within genotype revealed Mn^(2+)-enhanced MR signal as it proceeded from the injection site into the forebrain, the expected projection from CA3. By region of interest (ROI) analysis of the MSN, wide variation between individuals in each genotype was found. Despite this statistically significant intensity increases in the MSN at 6 hr post-injection was found in both genotypes, albeit less so in the KLC-KO. While the average accumulation at 6 hr was less in the KLC-KO, this difference did not reach significance. Projections of SPM T-maps for each genotype onto the same grayscale image revealed differences in the anatomical location of significant voxels. Although KLC-KO mice had smaller brains than wild-type, the gross anatomy was normal with no apparent loss of septal cholinergic neurons. Hence anatomy alone does not explain the differences in SPM maps. We conclude that kinesin-1 defects may have only a minor effect on the rate and distribution of transported Mn^(2+) within the living brain. This impairment is less than expected for this abundant microtubule-based motor, yet such defects could still be functionally significant, resulting in cognitive/emotional dysfunction due to decreased replenishments of synaptic vesicles or mitochondria during synaptic activity. This study demonstrates the power of MEMRI to observe and measure vesicular transport dynamics in the central nervous system that may result from or lead to brain pathology.", "doi": "10.1016/j.neuroimage.2016.09.035", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2017-01-15", "series_number": "Pt. A", "volume": "145", "issue": "Pt. A", "pages": "44-57" }, { "id": "authors:gf9ht-9mh65", "collection": "authors", "collection_id": "gf9ht-9mh65", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150504-134643774", "type": "conference_item", "title": "Witnessing microtubule-based transport in the living brain: Impact of the cargomotor receptor, amyloid precursor protein, and Alzheimer's plaques", "author": [ { "family_name": "Chaves", "given_name": "F. L.", "clpid": "Chaves-F-L" }, { "family_name": "Medina", "given_name": "C. S.", "clpid": "Medina-C-S" }, { "family_name": "Zhang", "given_name": "X.", "clpid": "Zhang-X" }, { "family_name": "Jacobs", "given_name": "R. E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" }, { "family_name": "Bearer", "given_name": "E. L.", "clpid": "Bearer-E-L" } ], "contributor": [ { "family_name": "Lippincott-Schwartz", "given_name": "Jennifer", "clpid": "Lippincott-Schwartz-J" }, { "family_name": "Marshall", "given_name": "Wallace", "clpid": "Marshall-W" }, { "family_name": "Marks", "given_name": "Michael", "clpid": "Marks-M" } ], "abstract": "Most amyloid precursor protein (APP)-based Alzheimer's models overexpress mutant human APP\nresulting in Abeta plaques. Yet the relative contribution of this elevated APP and the presence of\nplaques to neurodegeneration remains a big question. APP's role as a cargo-motor receptor for axonal\ntransport suggests that overexpression might lead to increased transport. Indeed we showed that\ntransport is increased in Down's syndrome and decreased in APP knockout mice. Hence transport may\nbe elevated in APP overexpressors and lead to either beneficial or deleterious consequences. Here we\nuse high field microMRI with Mn2+, an MR contrast agent useful as a track-tracer, to pose this cell\nbiological quest\nion within the whole living brains of wildtype and Alzheimer's model mice. Injection of\nMn2+ into the CA3 region of the hippocampus results in measurable transport over time. Application of\n3D unbiased whole brain image analysis detects all circuitry emanating from the hippocampus. By\ndriving APP Swe/Ind transgene expression with a tetracycline-sensitive promoter, APPSwe/Ind\nexpression can be decoupled from the presence of plaques with doxycycline (doxy). Three groups of\nmice were studied: group 'A' (no doxy, +plaques, +APP); group 'B' (doxy at 8 days before sacrifice,\n+plaques, no APP), and group 'C' (doxy prior to conception, and stopped 8 days before sacrifice, no\nplaques, +APP). Images were captured before and sequentionally after Mn2+ injection into CA\n3 (1, 7, 25\nhr). Images were aligned and analyzed by statistical parametric mapping to identify differential\naccumulation within the hippocampal projections. Histopathology revealed well-developed plaques in A\nand B, and Western blots showed human APP expressed five-fold over WT in in A and C. Our preliminary\nresults show increased transport in A and C, with APP Swe/Ind expression when compared with B,\nwhere expression is suppressed. Cholinergic neurons in the medial septal nucleus were decreased as\ndetermined by anti-ChAT staining in Group C (p=0.0006 by one-way ANOVA, n=15). In conclusion, the\neffects of elevated APP expression are separable from consequences of plaque, and each may.", "publisher": "Caltech Library", "publication_date": "2014-12" }, { "id": "authors:hf8jj-5qp84", "collection": "authors", "collection_id": "hf8jj-5qp84", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150504-140144268", "type": "conference_item", "title": "Developing a Model for Slow Hypoxic Injury and Vascular Degeneration in Amyloid Burdened Brains", "author": [ { "family_name": "Floruta", "given_name": "C. M.", "clpid": "Floruta-C-M" }, { "family_name": "Chaves", "given_name": "F. L.", "clpid": "Chaves-F-L" }, { "family_name": "Medina", "given_name": "C. S.", "clpid": "Medina-C-S" }, { "family_name": "Bearer", "given_name": "E. L.", "clpid": "Bearer-E-L" } ], "contributor": [ { "family_name": "Lippincott-Schwartz", "given_name": "Jennifer", "clpid": "Lippincott-Schwartz-J" }, { "family_name": "Marshall", "given_name": "Wallace", "clpid": "Marshall-W" }, { "family_name": "Marks", "given_name": "Michael", "clpid": "Marks-M" } ], "abstract": "The breakdown of neurovascular systems may play a crucial role in the pathogenesis of Alzheimer's\ndisease. However whether this breakdown initiates a degenerative mechanism or is the consequence of\nsome other deleterious process remains unknown. We examined hippocampal pathology in double\ntransgenic mice overexpressing a human mutant gene encoding the amyloid precursor protein\n(APPSwe/Ind) using a combination of histochemistry and stereologic techniques. Expression of\nAPPSwe/Ind in these mice is driven by a tetracycline-sensitive promoter. Tetracycline transcriptional\nactivator (tTA), the second transgene, is driven in turn by a CAM KIIa promoter that is only active in\nneurons. Thus this double transgenic construct allows us to control expression of APPSwe/Ind with\ndoxycycline. Utilizing this characteristic, we created three distinct experimental groups: A, display abeta\nplaque pathology and express APPSwe/Ind at time of sacrifice; B, display abeta plaque pathology but do\nnot express APPSwe/Ind at time of sacrifice; and C, do not display abeta plaque pathology but do\nexpress APPSwe/Ind at time of sacrifice. Stereologic investigation revealed decreased hippocampal\nvolume in groups A(n=5) and B(n=5) when compared to group C(n=5) and age-matched wildtype (n=9).", "publisher": "Caltech Library", "publication_date": "2014-12" }, { "id": "authors:hfdkc-9qg15", "collection": "authors", "collection_id": "hfdkc-9qg15", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130923-102549369", "type": "article", "title": "Mechanistic patient-specific predictive correlation of tumor drug response with microenvironment and perfusion measurements", "author": [ { "family_name": "Pascal", "given_name": "Jennifer", "clpid": "Pascal-J" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Wang", "given_name": "Zhihui", "clpid": "Wang-Zhihui" }, { "family_name": "Koay", "given_name": "Eugene J.", "clpid": "Koay-E-J" }, { "family_name": "Curley", "given_name": "Steven A.", "clpid": "Curley-S-A" }, { "family_name": "Cristini", "given_name": "Vittorio", "clpid": "Cristini-V" } ], "abstract": "Physical properties of the microenvironment influence penetration of drugs into tumors. Here, we develop a mathematical model to predict the outcome of chemotherapy based on the physical laws of diffusion. The most important parameters in the model are the volume fraction occupied by tumor blood vessels and their average diameter. Drug delivery to cells, and kill thereof, are mediated by these microenvironmental properties and affected by the diffusion penetration distance after extravasation. To calculate parameter values we fit the model to histopathology measurements of the fraction of tumor killed after chemotherapy in human patients with colorectal cancer metastatic to liver (coefficient of determination R^2 = 0.94). To validate the model in a different tumor type, we input patient-specific model parameter values from glioblastoma; the model successfully predicts extent of tumor kill after chemotherapy (R^2 = 0.7\u20130.91). Toward prospective clinical translation, we calculate blood volume fraction parameter values from in vivo contrast-enhanced computed tomography imaging from a separate cohort of patients with colorectal cancer metastatic to liver, and demonstrate accurate model predictions of individual patient responses (average relative error = 15%). Here, patient-specific data from either in vivo imaging or histopathology drives output of the model's formulas. Values obtained from standard clinical diagnostic measurements for each individual are entered into the model, producing accurate predictions of tumor kill after chemotherapy. Clinical translation will enable the rational design of individualized treatment strategies such as amount, frequency, and delivery platform of drug and the need for ancillary non\u2013drug-based treatment.", "doi": "10.1073/pnas.1300619110", "pmcid": "PMC3761643", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2013-08-27", "series_number": "35", "volume": "110", "issue": "35", "pages": "14266-14271" }, { "id": "authors:xtskb-hdv38", "collection": "authors", "collection_id": "xtskb-hdv38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20130405-103952676", "type": "article", "title": "Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse", "author": [ { "family_name": "Gallagher", "given_name": "Joseph J.", "clpid": "Gallagher-J-J" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Hall", "given_name": "F. Scott", "clpid": "Hall-F-S" }, { "family_name": "Uhl", "given_name": "George R.", "clpid": "Uhl-G-R" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of more robust connectivity in the frontal portion of the reward circuit of the DAT and NET knockout mice compared to the SERT knockout mice.", "doi": "10.1371/journal.pone.0057597", "pmcid": "PMC3587643", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2013-03-04", "series_number": "3", "volume": "8", "issue": "3", "pages": "Art. No. e57597" }, { "id": "authors:47ssh-kq786", "collection": "authors", "collection_id": "47ssh-kq786", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20120427-131435062", "type": "article", "title": "Deficits in axonal transport in hippocampal-based circuitry and the visual pathway in APP knock-out animals witnessed by manganese enhanced MRI", "author": [ { "family_name": "Gallagher", "given_name": "Joseph J.", "clpid": "Gallagher-J-J" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Ziomek", "given_name": "Gregory J.", "clpid": "Ziomek-G-J" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" } ], "abstract": "Mounting evidence implicates axonal transport defects, typified by the presence of axonal varicosities with aberrant accumulations of cargo, as an early event in Alzheimer's disease (AD) pathogenesis. Work identifying amyloid precursor protein (APP) as a vesicular motor receptor for anterograde axonal transport further implicates axonal transport in AD. Manganese-enhanced MRI (MEMRI) detects axonal transport dynamics in preclinical studies. Here we pursue an understanding of the role of APP in axonal transport in the central nervous system by applying MEMRI to hippocampal circuitry and to the visual pathway in living mice homozygous for either wild type or a deletion in the APP gene (n = 12 for each genotype). Following intra-ocular or stereotaxic hippocampal injection, we performed time-lapse MRI to detect Mn^(2+) transport. Three dimensional whole brain datasets were compared on a voxel-wise basis using within-group pair-wise analysis. Quantification of transport to structures connected to injection sites via axonal fiber tracts was also performed. Histology confirmed consistent placement of hippocampal injections and no observable difference in glial-response to the injections. APP\u2212/\u2212 mice had significantly reduced transport from the hippocampus to the septal nuclei and amygdala after 7 h and reduced transport to the contralateral hippocampus after 25 h; axonal transport deficits in the APP\u2212/\u2212 animals were also identified in the visual pathway. These data support a system-wide role for APP in axonal transport within the central nervous system and demonstrate the power of MEMRI for assessing neuronal circuitry involved in memory and learning.", "doi": "10.1016/j.neuroimage.2012.01.132", "pmcid": "PMC3328142", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2012-04-15", "series_number": "3", "volume": "60", "issue": "3", "pages": "1856-1866" }, { "id": "authors:vycar-8x947", "collection": "authors", "collection_id": "vycar-8x947", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20121220-104515211", "type": "article", "title": "Imaging functional anatomy in the brain of mouse models of human disease", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Gallagher", "given_name": "Joseph J.", "clpid": "Gallagher-J-J" }, { "family_name": "Gonzales", "given_name": "Aaron", "clpid": "Gonzales-A" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Defects in axonal transport have been implicated in a number of neurodegenerative diseases, from the poly-Q diseases like Huntington's disease, to Alzheimer's disease. The temporal sequence by which a pathological process unfolds is often unknown because our detection system relies on fixed tissue. Magnetic resonance imaging (MRI), a non-destructive imaging modality, allows longitudinal studies inside opaque structures in live animals. We use manganese-enhanced MRI (MEMRI) to witness axonal transport within the living brain of animal models of Alzheimer's disease. Mn2+ enters neurons and is transported by endogenous axonal transport. Thus MEMRI allows us for the first time to measure transport dynamics in the living brain. We find that in mice deleted for amyloid precursor protein (APP), a cargo-receptor for transport whose product is the main component of senile plaques, transport of Mn2+ is decreased in the optic nerve and in the important memory circuit from hippocampus to forebrain. Older mice over-expressing mutant APP also display decreased transport, demonstrating a bimodal effect of APP on transport dynamics. Using statistical parametric mapping of genotypic cohorts, sensitive quantitative measurements of transport are possible. Structural MRI also reveals volumetric changes over time. We conclude that MEMRI reveals pathological progression of disease processes in the living brain.", "issn": "0892-6638", "publisher": "Federation of American Societies for Experimental Biology", "publication": "FASEB Journal", "publication_date": "2012-04", "volume": "26", "pages": "Art. No. 398.2" }, { "id": "authors:qn9km-6jq02", "collection": "authors", "collection_id": "qn9km-6jq02", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100811-100757895", "type": "article", "title": "Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain", "author": [ { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Boulat", "given_name": "Benoit", "clpid": "Boulat-B" }, { "family_name": "Hall", "given_name": "F. Scott", "clpid": "Hall-F-S" }, { "family_name": "Uhl", "given_name": "George R.", "clpid": "Uhl-G-R" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here.", "doi": "10.1371/journal.pone.0011506", "pmcid": "PMC2901340", "issn": "1932-6203", "publisher": "Public Library of Science", "publication": "PLoS ONE", "publication_date": "2010-07-09", "series_number": "7", "volume": "5", "issue": "7", "pages": "Art. No. e11506" }, { "id": "authors:mb5r3-xgp16", "collection": "authors", "collection_id": "mb5r3-xgp16", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20100521-152642118", "type": "article", "title": "Increased anatomical detail by in vitro MR microscopy with a modified Golgi impregnation method", "author": [ { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Perles-Barbacaru", "given_name": "Adriana T.", "clpid": "Perles-Barbacaru-A-T" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Golgi impregnation is unique in its ability to display the dendritic trees and axons of large numbers of individual neurons by histology. Here we apply magnetic resonance microscopy to visualize the neuroanatomy of animal models by combining histologic fixation chemistry with paramagnetic contrast agents. Although there is some differential uptake of the standard small-molecular-weight contrast agents by different tissue types, detailed discrimination of tissue architecture in MR images does not approach that of standard histology. Our modified Golgi impregnation method significantly increases anatomic detail in magnetic resonance microscopy images. Fixed mouse brains were treated with a solution containing a paramagnetic contrast agent (gadoteridol) and potassium dichromate. Results demonstrate a specific contrast enhancement likely due to diamagnetic hexavalent chromium undergoing tissue specific reduction to paramagnetic trivalent chromium. This new method dramatically improves neuroanatomical contrast compared to conventional fixation, displaying detail approximating that of histologic specimens at low (4\u00d7) magnification.", "doi": "10.1002/mrm.22322", "pmcid": "PMC3387550", "issn": "1084-7529", "publisher": "Wiley", "publication": "Magnetic Resonance in Medicine", "publication_date": "2010-05", "series_number": "5", "volume": "63", "issue": "5", "pages": "1391-1397" }, { "id": "authors:mrwb1-g9188", "collection": "authors", "collection_id": "mrwb1-g9188", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090519-160159475", "type": "article", "title": "Reward circuitry is perturbed in the absence of the serotonin transporter", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Janvelyan", "given_name": "Davit", "clpid": "Janvelyan-D" }, { "family_name": "Boulat", "given_name": "Benoit", "clpid": "Boulat-B" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "The serotonin transporter (SERT) modulates the entire serotonergic system in the brain and influences both the dopaminergic and norepinephrinergic systems. These three systems are intimately involved in normal physiological functioning of the brain and implicated in numerous pathological conditions. Here we use high-resolution magnetic resonance imaging (MRI) and spectroscopy to elucidate the effects of disruption of the serotonin transporter in an animal model system: the SERT knock-out mouse. Employing manganese-enhanced MRI, we injected Mn^(2+) into the prefrontal cortex and obtained 3D MR images at specific time points in cohorts of SERT and normal mice. Statistical analysis of co-registered datasets demonstrated that active circuitry originating in the prefrontal cortex in the SERT knock-out is dramatically altered, with a bias towards more posterior areas (substantia nigra, ventral tegmental area, and Raph\u00e9 nuclei) directly involved in the reward circuit. Injection site and tracing were confirmed with traditional track tracers by optical microscopy. In contrast, metabolite levels were essentially normal in the SERT knock-out by in vivo magnetic resonance spectroscopy and little or no anatomical differences between SERT knock-out and normal mice were detected by MRI. These findings point to modulation of the limbic cortical\u2013ventral striatopallidal by disruption of SERT function. Thus, molecular disruptions of SERT that produce behavioral changes also alter the functional anatomy of the reward circuitry in which all the monoamine systems are involved.", "doi": "10.1016/j.neuroimage.2009.03.026", "pmcid": "PMC2693299", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2009-07-15", "series_number": "4", "volume": "46", "issue": "4", "pages": "1091-1104" }, { "id": "authors:e28xf-4v271", "collection": "authors", "collection_id": "e28xf-4v271", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20090715-155038217", "type": "article", "title": "Multiparameter computational modeling of tumor invasion", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Lowengrub", "given_name": "John S.", "clpid": "Lowengrub-J-S" }, { "family_name": "Frieboes", "given_name": "Hermann B.", "clpid": "Frieboes-H" }, { "family_name": "Chuang", "given_name": "Yao-Li", "clpid": "Chuang-Y-L" }, { "family_name": "Jin", "given_name": "Fang", "clpid": "Jin-F" }, { "family_name": "Wise", "given_name": "Stephen M.", "clpid": "Wise-S-M" }, { "family_name": "Ferrari", "given_name": "Mauro", "clpid": "Ferrari-M" }, { "family_name": "Agus", "given_name": "David B.", "clpid": "Agus-D-B" }, { "family_name": "Cristini", "given_name": "Vittorio", "clpid": "Cristini-V" } ], "abstract": "Clinical outcome prognostication in oncology is a guiding principle in therapeutic choice. A wealth of qualitative empirical evidence links disease progression with tumor morphology, histopathology, invasion, and associated molecular phenomena. However, the quantitative contribution of each of the known parameters in this progression remains elusive. Mathematical modeling can provide the capability to quantify the connection between variables governing growth, prognosis, and treatment outcome. By quantifying the link between the tumor boundary morphology and the invasive phenotype, this work provides a quantitative tool for the study of tumor progression and diagnostic/prognostic applications. This establishes a framework for monitoring system perturbation towards development of therapeutic strategies and correlation to clinical outcome for prognosis.\nMajor Findings: We apply a biologically founded, multiscale, mathematical model to identify and quantify tumor biologic and molecular properties relating to clinical and morphological phenotype and to demonstrate that tumor growth and invasion are predictable processes governed by biophysical laws, and regulated by heterogeneity in phenotypic, genotypic, and microenvironmental parameters. This heterogeneity drives migration and proliferation of more aggressive clones up cell substrate gradients within and beyond the central tumor mass, while often also inducing loss of cell adhesion. The model predicts that this process triggers a gross morphologic instability that leads to tumor invasion via individual cells, cell chains, strands, or detached clusters infiltrating into adjacent tissue producing the typical morphologic patterns seen, e.g., in the histopathology of glioblastoma multiforme. The model further predicts that these different morphologies of infiltration correspond to different stages of tumor progression regulated by heterogeneity.", "doi": "10.1158/0008-5472.CAN-08-3834", "issn": "0008-5472", "publisher": "American Association for Cancer Research", "publication": "Cancer Research", "publication_date": "2009-05-15", "series_number": "10", "volume": "69", "issue": "10", "pages": "4493-4501" }, { "id": "authors:q4pkr-hxc47", "collection": "authors", "collection_id": "q4pkr-hxc47", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160303-092016078", "type": "book_section", "title": "Imaging biophysics of axonal transport with MEMRI: Optic tract transport is altered in mouse model of Alzheimer's disease", "book_title": "17th annual ISMRM Scientific Meeting and Exhibition 2009", "author": [ { "family_name": "Bearer", "given_name": "E. L.", "clpid": "Bearer-E-L" }, { "family_name": "Zhang", "given_name": "X.", "clpid": "Zhang-X" }, { "family_name": "Biris", "given_name": "O.", "clpid": "Biris-O" }, { "family_name": "Jacobs", "given_name": "R. E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Recent evidence implicates transport defects in neurodegeneration, epilepsy, and glaucoma. The oriented neuronal projections from the retinal ganglion cells in the optic tract proved an excellent system in which to detect the effects of genetics or disease on axonal transport. Manganese-enhanced MRI (MEMRI) allows tracing of neuronal tracts in the optic tract of living animals, which thus offers the potential to measure the dynamics of axonal transport over time in genetically controlled animals (1, 2). We previously reported in timelapse MRI of intensity changes along the optic tract that Mn^(++) transports more slowly in the optic tract of mice with a genetic knock-out\nof the kinesin light chain gene (3). Conventional kinesin is the cellular motor thought to mediate a portion of axonal transport. This result demonstrated that MEMR imaging is sensitive enough to detect transport differences between genetically distinct mice. Here we report the effect of genetic manipulation of amyloid precursor protein (APP) on Mn^(++) transport by time-lapse T1-weighted slab images acquired at 6 min intervals over the course of 3.0 hr after injection of Mn^(++) into the posterior chamber of the eye. We tested 16 mo old mice expressing a human APP mutant protein known to cause Alzheimer's disease (SwAPP) and their wildtype littermates (TTA)(4). At this age, this mutant mouse strain has Alzheimer's-type plaques in the brain.", "pmcid": "PMC4509602", "isbn": "9781-615673384", "publisher": "International Society for Magnetic Resonance in Medicine", "place_of_publication": "Berkeley, CA", "publication_date": "2009-04", "pages": "40" }, { "id": "authors:bz4tj-m4c80", "collection": "authors", "collection_id": "bz4tj-m4c80", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:CUIpnas07", "type": "article", "title": "One at a time, live tracking of NGF axonal transport using quantum dots", "author": [ { "family_name": "Cui", "given_name": "Bianxiao", "clpid": "Cui-Bianxiao" }, { "family_name": "Wu", "given_name": "Chengbiao", "clpid": "Wu-Chengbiao" }, { "family_name": "Chen", "given_name": "Liang", "clpid": "Chen-Liang" }, { "family_name": "Ramirez", "given_name": "Alfredo", "clpid": "Ramirez-A" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Li", "given_name": "Wei-Ping", "clpid": "Li-Wei-Ping" }, { "family_name": "Mobley", "given_name": "William C.", "clpid": "Mobley-W-C" }, { "family_name": "Chu", "given_name": "Steven", "clpid": "Chu-Steven" } ], "abstract": "Retrograde axonal transport of nerve growth factor (NGF) signals is critical for the survival, differentiation, and maintenance of peripheral sympathetic and sensory neurons and basal forebrain cholinergic neurons. However, the mechanisms by which the NGF signal is propagated from the axon terminal to the cell body are yet to be fully elucidated. To gain insight into the mechanisms, we used quantum dot-labeled NGF (QD-NGF) to track the movement of NGF in real time in compartmentalized culture of rat dorsal root ganglion (DRG) neurons. Our studies showed that active transport of NGF within the axons was characterized by rapid, unidirectional movements interrupted by frequent pauses. Almost all movements were retrograde, but short-distance anterograde movements were occasionally observed. Surprisingly, quantitative analysis at the single molecule level demonstrated that the majority of NGF-containing endosomes contained only a single NGF dimer. Electron microscopic analysis of axonal vesicles carrying QD-NGF confirmed this finding. The majority of QD-NGF was found to localize in vesicles 50\u2013150 nm in diameter with a single lumen and no visible intralumenal membranous components. Our findings point to the possibility that a single NGF dimer is sufficient to sustain signaling during retrograde axonal transport to the cell body.", "doi": "10.1073/pnas.0706192104", "pmcid": "PMC1959439", "issn": "0027-8424", "publisher": "National Academy of Sciences", "publication": "Proceedings of the National Academy of Sciences of the United States of America", "publication_date": "2007-08-21", "series_number": "34", "volume": "104", "issue": "34", "pages": "13666-13671" }, { "id": "authors:dhrb8-wbj75", "collection": "authors", "collection_id": "dhrb8-wbj75", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160129-080803670", "type": "article", "title": "Live imaging of neuronal connections by magnetic resonance: Robust transport in the hippocampal\u2013septal memory circuit in a mouse model of Down syndrome", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Connections from hippocampus to septal nuclei have been implicated in memory loss and the cognitive impairment in Down syndrome (DS). We trace these connections in living mice by Mn^(2+) enhanced 3D MRI and compare normal with a trisomic mouse model of DS, Ts65Dn. After injection of 4 nl of 200 mM Mn^(2+) into the right hippocampus, Mn^(2+) enhanced circuitry was imaged at 0.5, 6, and 24 h in each of 13 different mice by high resolution MRI to detect dynamic changes in signal over time. The pattern of Mn^(2+) enhanced signal in vivo correlated with the histologic pattern in fixed brains of co-injected 3kD rhodamine\u2013dextran\u2013amine, a classic tracer. Statistical parametric mapping comparing intensity changes between different time points revealed that the dynamics of Mn2+ transport in this pathway were surprisingly more robust in DS mice than in littermate controls, with statistically significant intensity changes in DS appearing at earlier time points along expected pathways. This supports reciprocal alterations of transport in the hippocampal-forebrain circuit as being implicated in DS and argues against a general failure of transport. This is the first examination of in vivo transport dynamics in this pathway and the first report of elevated transport in DS.", "doi": "10.1016/j.neuroimage.2007.05.010", "pmcid": "PMC2074885", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2007-08-01", "series_number": "1", "volume": "37", "issue": "1", "pages": "230-242" }, { "id": "authors:827rd-3xt38", "collection": "authors", "collection_id": "827rd-3xt38", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20160127-155031136", "type": "article", "title": "Role of neuronal activity and kinesin on tract tracing by manganese-enhanced MRI (MEMRI)", "author": [ { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Falzone", "given_name": "Tom\u00e1s Luis", "clpid": "Falzone-T-L" }, { "family_name": "Zhang", "given_name": "Xiaowei", "clpid": "Zhang-Xiaowei" }, { "family_name": "Biris", "given_name": "Octavian", "clpid": "Biris-O" }, { "family_name": "Rasin", "given_name": "Arkady", "clpid": "Rasin-A" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "MEMRI offers the exciting possibility of tracing neuronal circuits in living animals by MRI. Here we use the power of mouse genetics and the simplicity of the visual system to test rigorously the parameters affecting Mn^(2+) uptake, transport and trans-synaptic tracing. By measuring electrical response to light before and after injection of Mn^(2+) into the eye, we determine the dose of Mn^(2+) with the least toxicity that can still be imaged by MR at 11.7 T. Using mice with genetic retinal blindness, we discover that electrical activity is not necessary for uptake and transport of Mn^(2+) in the optic nerve but is required for trans-synaptic transmission of this tracer to distal neurons in this pathway. Finally, using a kinesin light chain 1 knockout mouse, we find that conventional kinesin is a participant but not essential to neuronal transport of Mn^(2+) in the optic tract. This work provides a molecular and physiological framework for interpreting data acquired by MEMRI of circuitry in the brain.", "doi": "10.1016/j.neuroimage.2007.04.053", "pmcid": "PMC2096707", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2007", "series_number": "S1", "volume": "37", "issue": "S1", "pages": "S37-S46" }, { "id": "authors:5b3cc-wyj11", "collection": "authors", "collection_id": "5b3cc-wyj11", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20150908-164452714", "type": "article", "title": "Statistical diffusion tensor histology reveals regional dysmyelination effects in the shiverer mouse mutant", "author": [ { "family_name": "Tyszka", "given_name": "J. Michael", "orcid": "0000-0001-9342-9014", "clpid": "Tyszka-J-M" }, { "family_name": "Readhead", "given_name": "Carol", "clpid": "Readhead-Carol" }, { "family_name": "Bearer", "given_name": "Elaine L.", "clpid": "Bearer-E-L" }, { "family_name": "Pautler", "given_name": "Robia G.", "clpid": "Pautler-R-G" }, { "family_name": "Jacobs", "given_name": "Russell E.", "orcid": "0000-0002-1382-8486", "clpid": "Jacobs-R-E" } ], "abstract": "Shiverer is an important model of central nervous system dysmyelination characterized by a deletion in the gene encoding myelin basic protein with relevance to human dysmyelinating and demyelinating diseases. Perfusion fixed brains from shiverer mutant (C3Fe.SWV Mbp^(shi)/Mbp^(shi)n = 6) and background control (C3HeB.FeJ, n = 6) mice were compared using contrast enhanced volumetric diffusion tensor magnetic resonance microscopy with a nominal isotropic spatial resolution of 80 mum. Images were accurately coregistered using non-linear warping allowing voxel-wise statistical parametric mapping of tensor invariant differences between control and shiverer groups. Highly significant differences in the tensor trace and both the axial and radial diffusivity were observed within the major white matter tracts and in the thalamus, midbrain, brainstem and cerebellar white matter, consistent with a high density of myelinated axons within these regions. The fractional anisotropy was found to be much less sensitive than the trace and eigenvalues to dysmyelination and associated microanatomic changes.", "doi": "10.1016/j.neuroimage.2005.08.037", "pmcid": "PMC3376084", "issn": "1053-8119", "publisher": "Elsevier", "publication": "NeuroImage", "publication_date": "2006-02-15", "series_number": "4", "volume": "29", "issue": "4", "pages": "1058-1065" } ]