Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is broadly characterized by neurodegeneration, pathology accumulation, and cognitive decline. There is considerable variation in the progression of clinical symptoms and pathology in humans, highlighting the importance of genetic diversity in the study of AD. To address this, we analyze cell composition and amyloid-beta deposition of 6- and 14-month-old AD-BXD mouse brains. We utilize the analytical QUINT workflow- a suite of software designed to support atlas-based quantification, which we expand to deliver a highly effective method for registering and quantifying cell and pathology changes in diverse disease models. In applying the expanded QUINT workflow, we quantify near-global age-related increases in microglia, astrocytes, and amyloid-beta, and we identify strain-specific regional variation in neuron load. To understand how individual differences in cell composition affect the interpretation of bulk gene expression in AD, we combine hippocampal immunohistochemistry analyses with bulk RNA-sequencing data. This approach allows us to categorize genes whose expression changes in response to AD in a cell and/or pathology load-dependent manner. Ultimately, our study demonstrates the use of the QUINT workflow to standardize the quantification of immunohistochemistry data in diverse mice, - providing valuable insights into regional variation in cellular load and amyloid deposition in the AD-BXD model.

The Locare workflow: representing neuroscience data locations as geometric objects in 3D brain atlases.

Neuroscientists employ a range of methods and generate increasing amounts of data describing brain structure and function. The anatomical locations from which observations or measurements originate represent a common context for data interpretation, and a starting point for identifying data of interest. However, the multimodality and abundance of brain data pose a challenge for efforts to organize, integrate, and analyze data based on anatomical locations. While structured metadata allow faceted data queries, different types of data are not easily represented in a standardized and machine-readable way that allow comparison, analysis, and queries related to anatomical relevance. To this end, three-dimensional (3D) digital brain atlases provide frameworks in which disparate multimodal and multilevel neuroscience data can be spatially represented. We propose to represent the locations of different neuroscience data as geometric objects in 3D brain atlases. Such geometric objects can be specified in a standardized file format and stored as location metadata for use with different computational tools. We here present the Locare workflow developed for defining the anatomical location of data elements from rodent brains as geometric objects. We demonstrate how the workflow can be used to define geometric objects representing multimodal and multilevel experimental neuroscience in rat or mouse brain atlases. We further propose a collection of JSON schemas (LocareJSON) for specifying geometric objects by atlas coordinates, suitable as a starting point for co-visualization of different data in an anatomical context and for enabling spatial data queries.

Waxholm Space atlas of the rat brain: a 3D atlas supporting data analysis and integration.

Volumetric brain atlases are increasingly used to integrate and analyze diverse experimental neuroscience data acquired from animal models, but until recently a publicly available digital atlas with complete coverage of the rat brain has been missing. Here we present an update of the Waxholm Space rat brain atlas, a comprehensive open-access volumetric atlas resource. This brain atlas features annotations of 222 structures, of which 112 are new and 57 revised compared to previous versions. It provides a detailed map of the cerebral cortex, hippocampal region, striatopallidal areas, midbrain dopaminergic system, thalamic cell groups, the auditory system and main fiber tracts. We document the criteria underlying the annotations and demonstrate how the atlas with related tools and workflows can be used to support interpretation, integration, analysis and dissemination of experimental rat brain data.

AtOM, an ontology model to standardize use of brain atlases in tools, workflows, and data infrastructures.

Brain atlases are important reference resources for accurate anatomical description of neuroscience data. Open access, three-dimensional atlases serve as spatial frameworks for integrating experimental data and defining regions-of-interest in analytic workflows. However, naming conventions, parcellation criteria, area definitions, and underlying mapping methodologies differ considerably between atlases and across atlas versions. This lack of standardized description impedes use of atlases in analytic tools and registration of data to different atlases. To establish a machine-readable standard for representing brain atlases, we identified four fundamental atlas elements, defined their relations, and created an ontology model. Here we present our Atlas Ontology Model (AtOM) and exemplify its use by applying it to mouse, rat, and human brain atlases. We discuss how AtOM can facilitate atlas interoperability and data integration, thereby increasing compliance with the FAIR guiding principles. AtOM provides a standardized framework for communication and use of brain atlases to create, use, and refer to specific atlas elements and versions. We argue that AtOM will accelerate analysis, sharing, and reuse of neuroscience data.

Organization of projections from the entorhinal cortex to the hippocampal formation of the Egyptian fruit bat Rousettus aegyptiacus.

The hippocampal formation and entorhinal cortex are crucially involved in learning and memory as well as in spatial navigation. The conservation of these structures across the entire mammalian lineage demonstrates their importance. Information on a diverse set of spatially tuned neurons has become available, but we only have a rudimentary understanding of how anatomical network structure affects functional tuning. Bats are the only order of mammals that have evolved true flight, and with this specialization comes the need to navigate and behave in a three dimensional (3D) environment. Spatial tuning of cells in the entorhinal-hippocampal network of bats has been studied for some time, but whether the reported tuning in 3D is associated with changes in the entorhinal-hippocampal network is not known. Here we investigated the entorhinal-hippocampal projections in the Egyptian fruit bat (Rousettus aegyptiacus), by injecting chemical anterograde tracers in the entorhinal cortex. Detailed analyses of the terminations of these projections in the hippocampus showed that both the medial and lateral entorhinal cortex sent projections to the molecular layer of all subfields of the hippocampal formation. Our analyses showed that the terminal distributions of entorhinal fibers in the hippocampal formation of Egyptian fruit bats-including the proximo-distal and longitudinal topography and the layer-specificity-are similar to what has been described in other mammalian species such as rodents and primates. The major difference in entorhinal-hippocampal projections that was described to date between rodents and primates is in the terminal distribution of the DG projection. We found that bats have entorhinal-DG projections that seem more like those in primates than in rodents. It is likely that the latter projection in bats is specialized to the behavioral needs of this species, including 3D flight and long-distance navigation.

Detecting the effect of genetic diversity on brain composition in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is characterized by neurodegeneration, pathology accumulation, and progressive cognitive decline. There is significant variation in age at onset and severity of symptoms highlighting the importance of genetic diversity in the study of AD. To address this, we analyzed cell and pathology composition of 6- and 14-month-old AD-BXD mouse brains using the semi-automated workflow (QUINT); which we expanded to allow for nonlinear refinement of brain atlas-registration, and quality control assessment of atlas-registration and brain section integrity. Near global age-related increases in microglia, astrocyte, and amyloid-beta accumulation were measured, while regional variation in neuron load existed among strains. Furthermore, hippocampal immunohistochemistry analyses were combined with bulk RNA-sequencing results to demonstrate the relationship between cell composition and gene expression. Overall, the additional functionality of the QUINT workflow delivers a highly effective method for registering and quantifying cell and pathology changes in diverse disease models.

A Timm-Nissl multiplane microscopic atlas of rat brain zincergic terminal fields and metal-containing glia.

The ability of Timm's sulphide silver method to stain zincergic terminal fields has made it a useful neuromorphological marker. Beyond its roles in zinc-signalling and neuromodulation, zinc is involved in the pathophysiology of ischemic stroke, epilepsy, degenerative diseases and neuropsychiatric conditions. In addition to visualising zincergic terminal fields, the method also labels transition metals in neuronal perikarya and glial cells. To provide a benchmark reference for planning and interpretation of experimental investigations of zinc-related phenomena in rat brains, we have established a comprehensive repository of serial microscopic images from a historical collection of coronally, horizontally and sagittally oriented rat brain sections stained with Timm's method. Adjacent Nissl-stained sections showing cytoarchitecture, and customised atlas overlays from a three-dimensional rat brain reference atlas registered to each section image are included for spatial reference and guiding identification of anatomical boundaries. The Timm-Nissl atlas, available from EBRAINS, enables experimental researchers to navigate normal rat brain material in three planes and investigate the spatial distribution and density of zincergic terminal fields across the entire brain.

A neuroscientist's guide to using murine brain atlases for efficient analysis and transparent reporting.

Brain atlases are widely used in neuroscience as resources for conducting experimental studies, and for integrating, analyzing, and reporting data from animal models. A variety of atlases are available, and it may be challenging to find the optimal atlas for a given purpose and to perform efficient atlas-based data analyses. Comparing findings reported using different atlases is also not trivial, and represents a barrier to reproducible science. With this perspective article, we provide a guide to how mouse and rat brain atlases can be used for analyzing and reporting data in accordance with the FAIR principles that advocate for data to be findable, accessible, interoperable, and re-usable. We first introduce how atlases can be interpreted and used for navigating to brain locations, before discussing how they can be used for different analytic purposes, including spatial registration and data visualization. We provide guidance on how neuroscientists can compare data mapped to different atlases and ensure transparent reporting of findings. Finally, we summarize key considerations when choosing an atlas and give an outlook on the relevance of increased uptake of atlas-based tools and workflows for FAIR data sharing.

Brain-wide distribution of reporter expression in five transgenic tetracycline-transactivator mouse lines.

The spatial pattern of transgene expression in tetracycline-controlled mouse models is governed primarily by the driver line used to introduce the tetracycline-controlled transactivator (tTA). Detailed maps showing where each tTA driver activates expression are therefore essential for designing and using tet-regulated models, particularly in brain research where cell type and regional specificity determine the circuits affected by conditional gene expression. We have compiled a comprehensive online repository of serial microscopic images showing brain-wide reporter expression for five commonly used tTA driver lines. We have spatially registered all images to a common three-dimensional mouse brain anatomical reference atlas for direct comparison of spatial distribution across lines. The high-resolution images and associated metadata are shared via the web page of the EU Human Brain Project. Images can be inspected using an interactive viewing tool that includes an optional overlay feature providing anatomical delineations and reference atlas coordinates. Interactive viewing is supplemented by semi-quantitative analyses of expression levels within anatomical subregions for each tTA driver line.

Navigating the Murine Brain: Toward Best Practices for Determining and Documenting Neuroanatomical Locations in Experimental Studies.

In experimental neuroscientific research, anatomical location is a key attribute of experimental observations and critical for interpretation of results, replication of findings, and comparison of data across studies. With steadily rising numbers of publications reporting basic experimental results, there is an increasing need for integration and synthesis of data. Since comparison of data relies on consistently defined anatomical locations, it is a major concern that practices and precision in the reporting of location of observations from different types of experimental studies seem to vary considerably. To elucidate and possibly meet this challenge, we have evaluated and compared current practices for interpreting and documenting the anatomical location of measurements acquired from murine brains with different experimental methods. Our observations show substantial differences in approach, interpretation and reproducibility of anatomical locations among reports of different categories of experimental research, and strongly indicate that ambiguous reports of anatomical location can be attributed to missing descriptions. Based on these findings, we suggest a set of minimum requirements for documentation of anatomical location in experimental murine brain research. We furthermore demonstrate how these requirements have been applied in the EU Human Brain Project to optimize workflows for integration of heterogeneous data in common reference atlases. We propose broad adoption of some straightforward steps for improving the precision of location metadata and thereby facilitating interpretation, reuse and integration of data.

Comparative Contemplations on the Hippocampus.

The hippocampus in mammals is a morphologically well-defined structure, and so are its main subdivisions. To define the homologous structure in other vertebrate clades, using these morphological criteria has been difficult, if not impossible, since the typical mammalian morphology is absent. Although there seems to be consensus that the most medial part of the pallium represents the hippocampus in all vertebrates, there is no consensus on whether all mammalian hippocampal subdivisions are present in the derivatives of the medial pallium in all vertebrate groups. The aim of this paper is to explore the potential relevance of connections to define the hippocampus across vertebrates, with a focus on mammals, reptiles, and birds.