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Although the effects of genes and mutations in diseased and normal states can be studied with technologies like single-cell and RNA sequencing, crucial information is missing about the location and interactions of specific types of cells in a spatial and neural circuit context. Spatial omics fills this gap by combining omics data with tissue images to enable scientists to visualize gene and protein expression in a preserved tissue context.

In a recent Genetic Engineering & Biotechnology News webinar, Xiangmin Xu, PhD, Professor, Department of Anatomy and Neurobiology, and Director, Center for Neural Circuit Mapping (CNCM), University of California, Irvine, School of Medicine, discussed single-cell and spatial multiomics technologies and described how they can be used to improve the mechanistic understandings of brain circuit plasticity and neurodegenerative diseases.

Neuroscience Technology and Resource Hub

As a hub for new technology and resource development in the field of neuroscience, the main focus of the CNCM is to advance the study of neural circuits to define mechanisms and pathways that underlie neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. The CNCM works collaboratively, both within UCI as well as externally with other research institutions, to establish transformative and translational research programs focused on developing cures for treating human diseases of the nervous system.

Using the latest single-cell technologies, including two Vizgen® in situ single-cell, spatial omics MERSCOPE® instruments, coupled with functional circuit mapping and behavioral analysis, the CNCM aims to determine how the epigenome shapes neural circuit activity, learning, and memory behaviors that change with aging and Alzheimer’s disease (AD) progression. For example, Xu emphasized that MERFISH (Multiplexed Error- Robust Fluorescence In Situ Hybridization) has been a powerful approach in the CNCM’s recent studies.

Single-Cell Spatial Omics Analysis of Alzheimer’s Disease 

Genome-wide association studies (GWAS) have identified genetic variants associated with AD. Taking advantage of this information and available mice models, the CNCM team applied MERFISH to measure 300 RNA species to produce a large-scale, spatially resolved, single-cell gene expression atlas of AD.

Previous studies have analyzed spatial transcriptomics of neurodegeneration in aging and in microglia activation, proving the power of MERFISH in investigating transcriptomic dysregulation in the brain. However, attempts to analyze spatial molecular impacts of AD pathology in mouse models have been limited in cell type, spatial resolution, or the size of the imaged area.

Using four different mice genotypes, WT, 5XFAD, Trem2R47H, and 5XFAD/ Trem2R47H, the CNCM utilized MERFISH to analyze 19 coronal slices. This MERFISH-based study enabled a single-cell, brain-wide analysis of transcriptomic dysregulation. Spatial analysis identified unique glial and neuronal transcriptomic alterations induced independently by 5XFAD and Trem2R47H mutations, impacting inflammatory responses in microglia and astrocytes along with neural plasticity/learning- and memory-associated molecular responses in neurons.

Importantly, analysis of plaque proximity–induced transcriptomic dysregulation identified alterations in glia and multiple neuronal subtypes.

Branching out, the team also studied Huntington’s disease, which primarily affects the striatum region of the brain, to evaluate cell type–specific differential gene expression analysis using a MERFISH dataset from WT and R6/2 transgenic model mice.

New Tools Mean New Opportunities

According to Xu, recent progress in single-cell, spatial, and circuit omics allows the determination of  identities, locations, and circuitry of the specific cells affected by neurodegenerative diseases, including AD and Huntington’s disease. Technologies such as MERFISH and conceptual advances present opportunities for not only studying but also potentially treating circuits vulnerable in neurodegenerative diseases.

“We were an early adopter of the Vizgen technology. It is a great experience,” Xu highlighted. “This type of academic/industrial collaboration is mutually beneficial and should be highly encouraged whenever possible.”


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Watch the webinar presented by Dr. Xu today hubs.ly/Q025GMD00

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