Biology subjects

Hornburg, K. J.

Publications and source records attributed to Hornburg, K. J..

5 recordsLinked to original sources

bioRxiv2025

Global dissection of the impact of Alzheimer's disease on brain architecture and behavior: High resolution MRH resolves robust regional effects

Alzheimers disease (AD) affects brain regions with remarkable heterogeneity, but the precise impact of this disease on hundreds of small cortical, subcortical, and brainstem regions remains poorly defined. Here, as a prelude to testing preclinical models to prevent AD, we systematically quantified effects of human AD mutations in APP and PSEN1 on 231 regions and comprehensively evaluated changes in volume with unprecedented resolution in genetically diverse mice as a function of sex and genetic background. We studied 34 5XFAD F1 hybrids and 23 sibling controls at 14 months, evaluating learning and memory behaviors, followed by ex vivo diffusion tensor images (DTI) at 25 {micro}m resolution. We delineated 231 regions of interest (ROIs) bilaterally with high precision. Remarkably, we found bidirectional changes: marked volume increases (up to 10%) in neocortex, hippocampus, amygdala, and sensory nuclei, contrasted with decreases in striatum, pallidum, thalamus, hypothalamus, and most fiber tracts. These opposing effects are unrelated to amyloid load and are likely to reflect temporal gradients in susceptibility of ROIs. Effects are similar in both sexes but far more prominent in females. Genetic background strongly modulates penetrance of the human mutations with the AD-BXD77 F1 type having the greatest sensitivity. Light sheet microscopy and stereological analysis of NeuN+ neurons and amyloid {beta} aggregates in 22 regions revealed up to 20% loss of cells in CA3 and in anterior and intralaminar parts of the thalamus. Volumetric changes correlated with impaired fear acquisition and memory, with cases and controls often showing opposite relations between performance and regional volumes. These findings reveal unprecedented regional heterogeneity in AD progression and suggest therapeutic efficacy may vary substantially across genetic backgrounds and between sexes.

neuroscience↗

bioRxiv2024

An Open Resource: MR and light sheet microscopy stereotaxic atlas of the mouse brain

We have combined MR histology and light sheet microscopy (LSM) of five postmortem C57BL/6J mouse brains in a stereotaxic space based on micro-CT yielding a multimodal 3D atlas with the highest spatial and contrast resolution yet reported. Brains were imaged in situ with multi gradient echo (mGRE) and diffusion tensor imaging (DTI) at 15 m resolution ([~] 2.4 million times that of clinical MRI). Scalar images derived from the average DTI and mGRE provide unprecedented contrast in 14 complementary 3D volumes, each highlighting distinct histologic features. The same tissues scanned with LSM and registered into the stereotaxic space provide 17 different molecular cell type stains. The common coordinate framework labels (CCFv3) complete the multimodal atlas. The atlas has been used to correct distortions in the Allen Brain Atlas and harmonize it with Franklin Paxinos. It provides a unique resource for stereotaxic labeling of mouse brain images from many sources.

neuroscience↗

bioRxiv2022

HiDiver: A Suite of Methods to Merge Magnetic Resonance Histology, Light Sheet Microscopy, and Complete Brain Delineations

We have developed new imaging and computational workflows to produce accurately aligned multimodal 3D images of the mouse brain that exploit high resolution magnetic resonance histology (MRH) and light sheet microscopy (LSM) with fully rendered 3D reference delineations of brain structures. The suite of methods starts with the acquisition of geometrically accurate (in-skull) brain MRIs using multi-gradient echo (MGRE) and new diffusion tensor imaging (DTI) at an isotropic spatial resolution of 15 m. Whole brain connectomes are generated using over 100 diffusion weighted images acquired with gradients at uniformly spaced angles. Track density images are generated at a super-resolution of 5 m. Brains are dissected from the cranium, cleared with SHIELD, stained by immunohistochemistry, and imaged by LSM at 1.8 m/pixel. LSM channels are registered into the reference MRH space along with the Allen Brain Atlas (ABA) Common Coordinate Framework version 3 (CCFv3). The result is a high-dimensional integrated volume with registration (HiDiver) that has a global alignment accuracy of 10-50 m. HiDiver enables 3D quantitative and global analyses of cells, circuits, connectomes, and CNS regions of interest (ROIs). Throughput is sufficiently high that HiDiver is now being used in comprehensive quantitative studies of the impact of gene variants and aging on rodent brain cytoarchitecture.

neuroscience↗

bioRxiv2021

Multimodal Magnetic Resonance Histology and Light Sheet Imaging for Quantitative Neurogenetics of the Mouse

Paul Lauterbur closed his seminal paper on MRI with the statement that "zeugmatographic (imaging) techniques should find many useful applications in studies of the internal structures, states and composition of microscopic objects" [1]. Magnetic resonance microscopy was subsequently demonstrated in 1986 by three groups [2] [3] [4]. The application of MRI to the study of tissue structure, i.e. magnetic resonance histology (MRH) was suggested in 1993 [5]. MRH, while based on the same physical principals as MRI is something fundamentally different than the clinical exams which are typically limited to voxel dimensions of ~ 1 mm3. Preclinical imaging systems can acquire images with voxels ~ 1000 times smaller. The MR histology images presented here have been acquired at yet another factor of 1000 increase in spatial resolution. Figure S1 in the supplement shows a comparison of a state-of-the-art fractional anisotropy images of a C57 mouse brain in vivo @ 150 m resolution (voxel volume of 3.3 x10-3 mm3) with the atlas we have generated for this work at 15 m spatial resolution (voxel volume of 3.3 x 10-6 mm3). In previous work, we have demonstrated the utility of MR histology in neurogenetics at spatial/angular resolution of 45 m /46 angles [6]. At this spatial/angular resolution it is possible to map whole brain connectivity with high correspondence to retroviral tracers [7]. But the MRH derived connectomes can be derived in less than a day where the retroviral tracer studies require months/years [8]. The resolution index (angular samples/voxel volume) for this previous work was >500,000 [9]. Figure S2 shows a comparison between that previous work and the new atlas presented in this paper with a resolution index of 32 million. Light sheet microscopy (LSM) has undergone similar rapid evolution over the last 20 years. The invention of tissue clearing, advances in immunohistochemistry and development of selective plane illumination microscopy (SPIM) now make it possible to acquire whole mouse brain images at submicron spatial resolution with a vast array of cell specific markers [10] [11] [12] [13]. And these advantages can be realized in scan times of < 6hrs. The major limitation from these studies is the distortion in the tissue from dissection from the cranium, swelling from clearing and staining, and tissue damage from handling. We report here the merger of these two methods: O_LIMRH with the brain in the skull to provide accurate geometry, cytoarchitectural measures using scalar imaging metrics and whole brain connectivity at 15 m isotropic spatial resolution with super resolution track density images @ 5 m isotropic resolution; C_LIO_LIwhole brain multichannel LSM @ 1.8x1.8x4.0 m; C_LIO_LIa big image data infrastructure that enables label mapping from the atlas to the MR image, geometric correction to the light sheet data, label mapping to the light sheet volumes and quantitative extraction of regional cell density. These methods make it possible to generate a comprehensive collection of image derived phenotypes (IDP) of cells and circuits covering the whole mouse brain with throughput that can be scaled for quantitative neurogenetics. C_LI

neuroscience↗

bioRxiv2020

A time-course study of actively stained mouse brains: DTI parameter and connectomic stability over one year

While the application of diffusion tensor imaging (DTI), tractography, and connectomics to fixed ex-vivo tissue is a common practice today, there have been limited studies examining the effects of fixation on brain microstructure over extended periods. This time-course study reports the changes of regional brain volumes and diffusion scalar parameters, such as fractional anisotropy across twelve representative brain regions as measures of brain structural stability. The scalar DTI parameters and regional volumes were highly variable over the first two weeks after fixation. The same parameters were stable over a two to eight-week window after fixation which means confounds from tissue stability over that scanning window are minimal. Quantitative connectomes were analyzed over the same time period with extension out to one year. While there is some change in the scalar metrics at one year after fixation, these changes are sufficiently small, particularly in white matter to support reproducible connectomes over a period ranging from two weeks to one year post fixation. These findings delineate a stable scanning period during which brain volumes, diffusion scalar metrics and connectomes are remarkably stable.

neuroscience↗