RESUMEN
Recent large-scale collaborations are generating major surveys of cell types and connections in the mouse brain, collecting large amounts of data across modalities, spatial scales, and brain areas. Successful integration of these data requires a standard 3D reference atlas. Here, we present the Allen Mouse Brain Common Coordinate Framework (CCFv3) as such a resource. We constructed an average template brain at 10 µm voxel resolution by interpolating high resolution in-plane serial two-photon tomography images with 100 µm z-sampling from 1,675 young adult C57BL/6J mice. Then, using multimodal reference data, we parcellated the entire brain directly in 3D, labeling every voxel with a brain structure spanning 43 isocortical areas and their layers, 329 subcortical gray matter structures, 81 fiber tracts, and 8 ventricular structures. CCFv3 can be used to analyze, visualize, and integrate multimodal and multiscale datasets in 3D and is openly accessible (https://atlas.brain-map.org/).
Asunto(s)
Encéfalo/anatomía & histología , Encéfalo/metabolismo , Encéfalo/fisiología , Animales , Atlas como Asunto , Mapeo Encefálico/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Imagenología Tridimensional/métodos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Modern genetic approaches are powerful in providing access to diverse cell types in the brain and facilitating the study of their function. Here, we report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.
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Encéfalo/metabolismo , Técnicas de Inactivación de Genes/métodos , Genes Reporteros , Animales , Encéfalo/citología , Calcio/metabolismo , Línea Celular , Hibridación Fluorescente in Situ , Luz , Ratones , Ratones Transgénicos , Microscopía Fluorescente , Neuronas/metabolismo , Optogenética , ARN no Traducido/genética , Transgenes/genéticaRESUMEN
Dendritic and axonal morphology reflects the input and output of neurons and is a defining feature of neuronal types1,2, yet our knowledge of its diversity remains limited. Here, to systematically examine complete single-neuron morphologies on a brain-wide scale, we established a pipeline encompassing sparse labelling, whole-brain imaging, reconstruction, registration and analysis. We fully reconstructed 1,741 neurons from cortex, claustrum, thalamus, striatum and other brain regions in mice. We identified 11 major projection neuron types with distinct morphological features and corresponding transcriptomic identities. Extensive projectional diversity was found within each of these major types, on the basis of which some types were clustered into more refined subtypes. This diversity follows a set of generalizable principles that govern long-range axonal projections at different levels, including molecular correspondence, divergent or convergent projection, axon termination pattern, regional specificity, topography, and individual cell variability. Although clear concordance with transcriptomic profiles is evident at the level of major projection type, fine-grained morphological diversity often does not readily correlate with transcriptomic subtypes derived from unsupervised clustering, highlighting the need for single-cell cross-modality studies. Overall, our study demonstrates the crucial need for quantitative description of complete single-cell anatomy in cell-type classification, as single-cell morphological diversity reveals a plethora of ways in which different cell types and their individual members may contribute to the configuration and function of their respective circuits.
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Encéfalo/citología , Forma de la Célula , Neuronas/clasificación , Neuronas/metabolismo , Análisis de la Célula Individual , Atlas como Asunto , Biomarcadores/metabolismo , Encéfalo/anatomía & histología , Encéfalo/embriología , Encéfalo/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Neocórtex/anatomía & histología , Neocórtex/citología , Neocórtex/embriología , Neocórtex/metabolismo , Neurogénesis , Neuroglía/citología , Neuronas/citología , RNA-Seq , Reproducibilidad de los ResultadosRESUMEN
An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted1. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-based anatomical description of one exemplar brain structure, the mouse primary motor cortex, upper limb area (MOp-ul). Using genetic and viral labelling, barcoded anatomy resolved by sequencing, single-neuron reconstruction, whole-brain imaging and cloud-based neuroinformatics tools, we delineated the MOp-ul in 3D and refined its sublaminar organization. We defined around two dozen projection neuron types in the MOp-ul and derived an input-output wiring diagram, which will facilitate future analyses of motor control circuitry across molecular, cellular and system levels. This work provides a roadmap towards a comprehensive cellular-resolution description of mammalian brain architecture.
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Corteza Motora/anatomía & histología , Corteza Motora/citología , Neuronas/clasificación , Animales , Atlas como Asunto , Femenino , Neuronas GABAérgicas/citología , Neuronas GABAérgicas/metabolismo , Glutamatos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuroimagen , Neuronas/citología , Neuronas/metabolismo , Especificidad de Órganos , Análisis de Secuencia de ARN , Análisis de la Célula IndividualRESUMEN
The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource1, involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network.
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Corteza Cerebral/anatomía & histología , Corteza Cerebral/citología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/citología , Tálamo/anatomía & histología , Tálamo/citología , Animales , Axones/fisiología , Corteza Cerebral/fisiología , Femenino , Integrasas/genética , Integrasas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/fisiología , Tálamo/fisiologíaRESUMEN
The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.
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Perfilación de la Expresión Génica , Neocórtex/citología , Neocórtex/metabolismo , Animales , Biomarcadores/análisis , Femenino , Neuronas GABAérgicas/metabolismo , Ácido Glutámico/metabolismo , Masculino , Ratones , Corteza Motora/anatomía & histología , Corteza Motora/citología , Corteza Motora/metabolismo , Neocórtex/anatomía & histología , Especificidad de Órganos , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Corteza Visual/anatomía & histología , Corteza Visual/citología , Corteza Visual/metabolismoRESUMEN
Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.
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Encéfalo/anatomía & histología , Encéfalo/citología , Conectoma , Animales , Atlas como Asunto , Axones/fisiología , Corteza Cerebral/citología , Cuerpo Estriado/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Neurológicos , Técnicas de Trazados de Vías Neuroanatómicas , Tálamo/citologíaRESUMEN
Establishment of the corpus callosum involves coordination between callosal projection neurons and multiple midline structures, including the glial wedge (GW) rostrally and hippocampal commissure caudally. GW defects have been associated with agenesis of the corpus callosum (ACC). Here we show that conditional Lhx2 inactivation in cortical radial glia using Emx1-Cre or Nestin-Cre drivers results in ACC. The ACC phenotype was characterized by aberrant ventrally projecting callosal axons rather than Probst bundles, and was 100% penetrant on 2 different mouse strain backgrounds. Lhx2 inactivation in postmitotic cortical neurons using Nex-Cre mice did not result in ACC, suggesting that the mutant phenotype was not autonomous to the callosal projection neurons. Instead, ACC was associated with an absent hippocampal commissure and a markedly reduced to absent GW. Expression studies demonstrated strong Lhx2 expression in the normal GW and in its radial glial progenitors, with absence of Lhx2 resulting in normal Emx1 and Sox2 expression, but premature exit from the cell cycle based on EdU-Ki67 double labeling. These studies define essential roles for Lhx2 in GW, hippocampal commissure, and corpus callosum formation, and suggest that defects in radial GW progenitors can give rise to ACC.
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Agenesia del Cuerpo Calloso/genética , Agenesia del Cuerpo Calloso/patología , Proteínas con Homeodominio LIM/genética , Mutación/genética , Neuroglía/patología , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Factores de Transcripción/genética , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Proteína Ácida Fibrilar de la Glía/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neocórtex/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Nestina/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , Proteínas Represoras/metabolismo , Proteínas de Dominio T Box , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The neocortex contains diverse populations of excitatory neurons segregated by layer and further definable by their specific cortical and subcortical projection targets. The current study describes a systematic approach to identify molecular correlates of specific projection neuron classes in mouse primary somatosensory cortex (S1), using a combination of in situ hybridization (ISH) data mining, marker gene colocalization, and combined retrograde labeling with ISH for layer-specific marker genes. First, we identified a large set of genes with specificity for each cortical layer, and that display heterogeneous patterns within those layers. Using these genes as markers, we find extensive evidence for the covariation of gene expression and projection target specificity in layer 2/3, 5, and 6, with individual genes labeling neurons projecting to specific subsets of target structures. The combination of gene expression and target specificity imply a great diversity of projection neuron classes that is similar to or greater than that of GABAergic interneurons. The covariance of these 2 phenotypic modalities suggests that these classes are both discrete and genetically specified.
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Neuronas/citología , Neuronas/fisiología , Corteza Somatosensorial/citología , Corteza Somatosensorial/fisiología , Animales , Atlas como Asunto , Minería de Datos , Expresión Génica/fisiología , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Vías Nerviosas/citología , Vías Nerviosas/fisiología , Trazadores del Tracto NeuronalRESUMEN
Müller glia are the primary glial subtype in the retina and perform a wide range of physiological tasks in support of retinal function, but little is known about the transcriptional network that maintains these cells in their differentiated state. We report that selective deletion of the LIM homeodomain transcription factor Lhx2 from mature Müller glia leads to the induction of reactive retinal gliosis in the absence of injury. Furthermore, Lhx2 expression is also down-regulated in Prph2(Rd2/Rd2) animals immediately before the onset of reactive gliosis. Analysis of conditional Lhx2 knockouts showed that gliosis was hypertrophic but not proliferative. Aging of experimental animals demonstrated that constitutive reactive gliosis induced by deletion of Lhx2 reduced rates of ongoing apoptosis and compromised both rod and cone photoreceptor function. Additionally, these animals showed a dramatically reduced ability to induce expression of secreted neuroprotective factors and displayed enhanced rates of apoptosis in light-damage assays. We provide in vivo evidence that Lhx2 actively maintains mature Müller glia in a nonreactive state, with loss of function initiating a specific program of nonproliferative hypertrophic gliosis.
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Gliosis/patología , Proteínas con Homeodominio LIM/fisiología , Retina/patología , Factores de Transcripción/fisiología , Animales , Antineoplásicos Hormonales/farmacología , Regulación de la Expresión Génica , Gliosis/genética , Proteínas con Homeodominio LIM/genética , Luz , Ratones , Ratones Noqueados , Modelos Biológicos , Enfermedades Neurodegenerativas/metabolismo , Neuroglía/fisiología , Estructura Terciaria de Proteína , Retina/fisiología , Tamoxifeno/farmacología , Factores de Transcripción/genéticaRESUMEN
The Allen Mouse Brain Connectivity Atlas consists of anterograde tracing experiments targeting diverse structures and classes of projecting neurons. Beyond regional anterograde tracing done in C57BL/6 wild-type mice, a large fraction of experiments are performed using transgenic Cre-lines. This allows access to cell-class-specific whole-brain connectivity information, with class defined by the transgenic lines. However, even though the number of experiments is large, it does not come close to covering all existing cell classes in every area where they exist. Here, we study how much we can fill in these gaps and estimate the cell-class-specific connectivity function given the simplifying assumptions that nearby voxels have smoothly varying projections, but that these projection tensors can change sharply depending on the region and class of the projecting cells. This paper describes the conversion of Cre-line tracer experiments into class-specific connectivity matrices representing the connection strengths between source and target structures. We introduce and validate a novel statistical model for creation of connectivity matrices. We extend the Nadaraya-Watson kernel learning method that we previously used to fill in spatial gaps to also fill in gaps in cell-class connectivity information. To do this, we construct a "cell-class space" based on class-specific averaged regionalized projections and combine smoothing in 3D space as well as in this abstract space to share information between similar neuron classes. Using this method, we construct a set of connectivity matrices using multiple levels of resolution at which discontinuities in connectivity are assumed. We show that the connectivities obtained from this model display expected cell-type- and structure-specific connectivities. We also show that the wild-type connectivity matrix can be factored using a sparse set of factors, and analyze the informativeness of this latent variable model.
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The claustrum (CLA) is a conspicuous subcortical structure interconnected with cortical and subcortical regions. Its regional anatomy and cell-type-specific connections in the mouse remain not fully determined. Using multimodal reference datasets, we confirmed the delineation of the mouse CLA as a single group of neurons embedded in the agranular insular cortex. We quantitatively investigated brain-wide inputs and outputs of CLA using bulk anterograde and retrograde viral tracing data and single neuron tracing data. We found that the prefrontal module has more cell types projecting to the CLA than other cortical modules, with layer 5 IT neurons predominating. We found nine morphological types of CLA principal neurons that topographically innervate functionally linked cortical targets, preferentially the midline cortical areas, secondary motor area, and entorhinal area. Together, this study provides a detailed wiring diagram of the cell-type-specific connections of the mouse CLA, laying a foundation for studying its functions at the cellular level.
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Claustro , Corteza Motora , Ratones , Animales , Claustro/fisiología , Vías Nerviosas/fisiología , Corteza Entorrinal/fisiología , NeuronasRESUMEN
Identification of structural connections between neurons is a prerequisite to understanding brain function. Here we developed a pipeline to systematically map brain-wide monosynaptic input connections to genetically defined neuronal populations using an optimized rabies tracing system. We used mouse visual cortex as the exemplar system and revealed quantitative target-specific, layer-specific and cell-class-specific differences in its presynaptic connectomes. The retrograde connectivity indicates the presence of ventral and dorsal visual streams and further reveals topographically organized and continuously varying subnetworks mediated by different higher visual areas. The visual cortex hierarchy can be derived from intracortical feedforward and feedback pathways mediated by upper-layer and lower-layer input neurons. We also identify a new role for layer 6 neurons in mediating reciprocal interhemispheric connections. This study expands our knowledge of the visual system connectomes and demonstrates that the pipeline can be scaled up to dissect connectivity of different cell populations across the mouse brain.
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Conectoma , Corteza Visual , Ratones , Animales , Neuronas/fisiología , Encéfalo/fisiología , Corteza Visual/fisiología , Vías VisualesRESUMEN
The mammalian brain is composed of diverse neuron types that play different functional roles. Recent single-cell RNA sequencing approaches have led to a whole brain taxonomy of transcriptomically-defined cell types, yet cell type definitions that include multiple cellular properties can offer additional insights into a neuron's role in brain circuits. While the Patch-seq method can investigate how transcriptomic properties relate to the local morphological and electrophysiological properties of cell types, linking transcriptomic identities to long-range projections is a major unresolved challenge. To address this, we collected coordinated Patch-seq and whole brain morphology data sets of excitatory neurons in mouse visual cortex. From the Patch-seq data, we defined 16 integrated morpho-electric-transcriptomic (MET)-types; in parallel, we reconstructed the complete morphologies of 300 neurons. We unified the two data sets with a multi-step classifier, to integrate cell type assignments and interrogate cross-modality relationships. We find that transcriptomic variations within and across MET-types correspond with morphological and electrophysiological phenotypes. In addition, this variation, along with the anatomical location of the cell, can be used to predict the projection targets of individual neurons. We also shed new light on infragranular cell types and circuits, including cell-type-specific, interhemispheric projections. With this approach, we establish a comprehensive, integrated taxonomy of excitatory neuron types in mouse visual cortex and create a system for integrated, high-dimensional cell type classification that can be extended to the whole brain and potentially across species.
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A crucial step in eye organogenesis is the transition of the optic vesicle into the optic cup. Several transcription factors and extracellular signals mediate this transition, but whether a single factor links them into a common genetic network is unclear. Here, we provide evidence that the LIM homeobox gene Lhx2, which is expressed in the optic neuroepithelium, fulfils such a role. In Lhx2(-/-) mouse embryos, eye field specification and optic vesicle morphogenesis occur, but development arrests prior to optic cup formation in both the optic neuroepithelium and lens ectoderm. This is accompanied by failure to maintain or initiate the expression patterns of optic-vesicle-patterning and lens-inducing determinants. Of the signaling pathways examined, only BMP signaling is noticeably altered and Bmp4 and Bmp7 mRNAs are undetectable. Lhx2(-/-) optic vesicles and lens ectoderm upregulate Pax2, Fgf15 and Sox2 in response to BMP treatments, and Lhx2 genetic mosaics reveal that transcription factors, including Vsx2 and Mitf, require Lhx2 cell-autonomously for their expression. Our data indicate that Lhx2 is required for optic vesicle patterning and lens formation in part by regulating BMP signaling in an autocrine manner in the optic neuroepithelium and in a paracrine manner in the lens ectoderm. We propose a model in which Lhx2 is a central link in a genetic network that coordinates the multiple pathways leading to optic cup formation.
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Ojo/embriología , Proteínas de Homeodominio/fisiología , Organogénesis/fisiología , Factores de Transcripción/fisiología , Animales , Tipificación del Cuerpo/genética , Embrión de Mamíferos , Técnica del Anticuerpo Fluorescente Directa , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Inmunohistoquímica , Hibridación in Situ , Proteínas con Homeodominio LIM , Ratones , Ratones Noqueados , Ratones Transgénicos , Mutación , Técnicas de Cultivo de Órganos , Organogénesis/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The evolutionarily conserved default mode network (DMN) is a distributed set of brain regions coactivated during resting states that is vulnerable to brain disorders. How disease affects the DMN is unknown, but detailed anatomical descriptions could provide clues. Mice offer an opportunity to investigate structural connectivity of the DMN across spatial scales with cell-type resolution. We co-registered maps from functional magnetic resonance imaging and axonal tracing experiments into the 3D Allen mouse brain reference atlas. We find that the mouse DMN consists of preferentially interconnected cortical regions. As a population, DMN layer 2/3 (L2/3) neurons project almost exclusively to other DMN regions, whereas L5 neurons project in and out of the DMN. In the retrosplenial cortex, a core DMN region, we identify two L5 projection types differentiated by in- or out-DMN targets, laminar position, and gene expression. These results provide a multi-scale description of the anatomical correlates of the mouse DMN.
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Encéfalo/diagnóstico por imagen , Red en Modo Predeterminado/diagnóstico por imagen , Red Nerviosa/diagnóstico por imagen , Neuronas/fisiología , Animales , Encéfalo/citología , Conectoma , Red en Modo Predeterminado/citología , Imagen por Resonancia Magnética , Ratones , Red Nerviosa/citología , Neuronas/citologíaRESUMEN
Subicular regions play important roles in spatial processing and many cognitive functions, and these are mainly attributed to the subiculum (Sub) rather than the prosubiculum (PS). Using single-cell RNA sequencing, we identify 27 transcriptomic cell types residing in sub-domains of the Sub and PS. Based on in situ expression of reliable transcriptomic markers, the precise boundaries of the Sub and PS are consistently defined along the dorsoventral axis. Using these borders to evaluate Cre-line specificity and tracer injections, we find bona fide Sub projections topographically to structures important for spatial processing and navigation. In contrast, the PS sends its outputs to widespread brain regions crucial for motivation, emotion, reward, stress, anxiety, and fear. The Sub and PS, respectively, dominate dorsal and ventral subicular regions and receive different afferents. These results reveal two molecularly and anatomically distinct circuits centered in the Sub and PS, respectively, providing a consistent explanation for historical data and a clearer foundation for future studies.
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Hipocampo/fisiopatología , Vías Nerviosas/metabolismo , Transcriptoma/genética , AnimalesRESUMEN
A variety of Alzheimer's disease (AD) mouse models overexpress mutant forms of human amyloid precursor protein (APP), producing high levels of amyloid ß (Aß) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aß deposition in brains of AD patients is unknown. Here, we mapped the spatial distribution of Aß plaques across age in three APP-overexpression mouse lines (APP/PS1, Tg2576, and hAPP-J20) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using custom-built segmentation algorithms. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In both APP/PS1 and Tg2576 mice, plaques were identified first in isocortex, followed by olfactory, hippocampal, and cortical subplate areas. In hAPP-J20 mice, plaque density was highest in hippocampal areas, followed by isocortex, with little to no involvement of olfactory or cortical subplate areas. Within the major brain divisions, distinct regions were identified with high (or low) plaque accumulation; for example, the lateral visual area within the isocortex of APP/PS1 mice had relatively higher plaque density compared with other cortical areas, while in hAPP-J20 mice, plaques were densest in the ventral retrosplenial cortex. In summary, we show how whole brain imaging of amyloid pathology in mice reveals the extent to which a given model recapitulates the regional Aß deposition patterns described in AD.
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Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides , Encéfalo/patología , Neuroimagen/métodos , Animales , Modelos Animales de Enfermedad , Procesamiento de Imagen Asistido por Computador , Ratones , Ratones TransgénicosRESUMEN
Understanding how >30 types of retinal ganglion cells (RGCs) in the mouse retina each contribute to visual processing in the brain will require more tools that label and manipulate specific RGCs. We screened and analyzed retinal expression of Cre recombinase using 88 transgenic driver lines. In many lines, Cre was expressed in multiple RGC types and retinal cell classes, but several exhibited more selective expression. We comprehensively mapped central projections from RGCs labeled in 26 Cre lines using viral tracers, high-throughput imaging, and a data processing pipeline. We identified over 50 retinorecipient regions and present a quantitative retina-to-brain connectivity map, enabling comparisons of target-specificity across lines. Projections to two major central targets were notably correlated: RGCs projecting to the outer shell or core regions of the lateral geniculate projected to superficial or deep layers within the superior colliculus, respectively. Retinal images and projection data are available online at http://connectivity.brain-map.org.
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Retina/fisiología , Células Ganglionares de la Retina/fisiología , Vías Visuales/fisiología , Animales , Integrasas/metabolismo , Ratones , Ratones Transgénicos , Retina/metabolismo , Células Ganglionares de la Retina/metabolismo , Colículos Superiores/metabolismo , Colículos Superiores/fisiologíaRESUMEN
Significant advances in circuit-level analyses of the brain require tools that allow for labeling, modulation of gene expression, and monitoring and manipulation of cellular activity in specific cell types and/or anatomical regions. Large-scale projects and individual laboratories have produced hundreds of gene-specific promoter-driven Cre mouse lines invaluable for enabling genetic access to subpopulations of cells in the brain. However, the potential utility of each line may not be fully realized without systematic whole brain characterization of transgene expression patterns. We established a high-throughput in situ hybridization (ISH), imaging and data processing pipeline to describe whole brain gene expression patterns in Cre driver mice. Currently, anatomical data from over 100 Cre driver lines are publicly available via the Allen Institute's Transgenic Characterization database, which can be used to assist researchers in choosing the appropriate Cre drivers for functional, molecular, or connectional studies of different regions and/or cell types in the brain.