EASI-FISH for thick tissue defines lateral hypothalamus spatio-molecular organization

Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We developed Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to survey gene expr...

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Bibliographic Details
Published in:Cell Vol. 184; no. 26; p. 6361
Main Authors: Wang, Yuhan, Eddison, Mark, Fleishman, Greg, Weigert, Martin, Xu, Shengjin, Wang, Tim, Rokicki, Konrad, Goina, Cristian, Henry, Fredrick E, Lemire, Andrew L, Schmidt, Uwe, Yang, Hui, Svoboda, Karel, Myers, Eugene W, Saalfeld, Stephan, Korff, Wyatt, Sternson, Scott M, Tillberg, Paul W
Format: Journal Article
Language:English
Published: United States 22.12.2021
Subjects:
Animals
Biomarkers - metabolism
Gene Expression Profiling
Gene Expression Regulation
Hypothalamic Area, Lateral - cytology
Hypothalamic Area, Lateral - metabolism
Imaging, Three-Dimensional
In Situ Hybridization, Fluorescence
Male
Mice
Mice, Inbred C57BL
Neurons - metabolism
Neuropeptides - metabolism
Proto-Oncogene Proteins c-fos - metabolism
RNA - metabolism
RNA-Seq
Single-Cell Analysis
Transcription, Genetic
expansion microscopy
RNA
brain anatomy
Fluorescence in situ hybridization
lateral hypothalamus
transcriptomics
3D segmentation
cell type
brain
ISSN:1097-4172, 1097-4172
Online Access:Get more information
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Summary:Determining the spatial organization and morphological characteristics of molecularly defined cell types is a major bottleneck for characterizing the architecture underpinning brain function. We developed Expansion-Assisted Iterative Fluorescence In Situ Hybridization (EASI-FISH) to survey gene expression in brain tissue, as well as a turnkey computational pipeline to rapidly process large EASI-FISH image datasets. EASI-FISH was optimized for thick brain sections (300 μm) to facilitate reconstruction of spatio-molecular domains that generalize across brains. Using the EASI-FISH pipeline, we investigated the spatial distribution of dozens of molecularly defined cell types in the lateral hypothalamic area (LHA), a brain region with poorly defined anatomical organization. Mapping cell types in the LHA revealed nine spatially and molecularly defined subregions. EASI-FISH also facilitates iterative reanalysis of scRNA-seq datasets to determine marker-genes that further dissociated spatial and morphological heterogeneity. The EASI-FISH pipeline democratizes mapping molecularly defined cell types, enabling discoveries about brain organization.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2021.11.024