Cellular-resolution in situ transcriptomics of the mouse brain and Alzheimer's disease models

点击翻译按钮获取中文摘要

The brain is composed of hundreds of subtly-different cell types, spread over hundreds of distinct regions. The sensory, motor, and cognitive functions the brain produces, arise from circuits distributed globally across these regions. To understand brain function, it is therefore essential to understand the global spatial organization of its component cell types. Similarly, to understand how cognition can falter in disease conditions, it is essential to understand how pathologies affect circuits across the whole brain.Alzheimer's disease is a devastating disorder of brain function, with a tremendous and still growing social and economic cost. Although much research has focused on a small set of regions (the hippocampus and entorhinal cortex), Alzheimer's disease affects the whole brain. For example, drugs targeting a small but very specific circuit, the basal forebrain cholinergic system, are amongst the few treatments approved for relief of Alzheimer's symptoms. Many other specific brain regions are likely to be involved also, but an understanding of the brain-wide pathology of the disease is currently lacking. Each brain region contains many finely-distinguished subtypes of neurons, as well as other cell types such as microglia, astrocytes, oligodendrocytes, and vascular cells, which all likely play a role in the disease aetiology. Precious little information is available on how these fine subtypes are involved in the disease. This project will employ a new technology, called in situ transcriptomics, to understand the global structure of the brain, and it is disrupted by the pathologies underlying Alzheimer's disease, using mouse models. This technology can localize the expression of many genes simultaneously, to sub-micrometer resolution, in samples of any tissue from any species. Because different cell types express different combinatorial patterns of genes, parallel measurement of a cell's gene expression profiles allows fine cell type classification. Furthermore, because changes in cellular function are almost always reflected in changes in gene expression, applying the technology to disease models will allow scientists to understand how the function of each cell type changes under pathological conditions.The technology is still under development, and is currently found in only a few labs worldwide. Our group at UCL are one of the developers of the technology. We have recently developed it to a point where it can localize up to 1000 genes simultaneously at high efficiency, and automated it so that it can run at high enough throughput to process an entire mouse brain. We propose here to apply this newly-established technology at scale, to produce an entire atlas of expression of 1000 carefully chosen genes, at submicron resolution, across the whole mouse brain. We will use this to spatially localize all the brain's cell types (building on work from a previous non-spatial transcriptomic technology). We will then apply the same methodology to two mouse lines, that model the two main types of pathology underlying Alzheimer's disease: the APPNL-G-F amyloid model, and the THY-Tau22 model. This will enable us to see how multiple types of neuron and non-neurons across all brain regions are affected by the amyloid and tau pathologies. All data will be made freely available, enabling scientists worldwide to use it to guide new experiments and hypotheses regarding the function of the healthy and diseased brain. This will provide foundational information, greatly accelerating progress towards understanding not only Alzheimers but also a wide range of other neurological and psychiatric disorders of cognition including for example schizophrenia, depression, bipolar disorder, frontotemporal dementia, Parkinson's disease, and Huntington's disease.