Integrated Brain Atlas for Unbiased Mapping of Nervous System Effects Following Liraglutide Treatment

Casper Bo Gravesen Salinas,Aaron Jeffrey Mercer,Anders Bjorholm Dahl,Anna Secher,Sanaz Gabery,Lotte Bjerre Knudsen,Jacob Hecksher-Sørensen,Tess Tsai-Hsiu Lu,Kasper Marstal,Anda Cornea,Knut Conradsen,Tomas Alanentalo

doi:10.1038/s41598-018-28496-6

Abstract

Light Sheet Fluorescence Microscopy (LSFM) of whole organs, in particular the brain, offers a plethora of biological data imaged in 3D. This technique is however often hindered by cumbersome non-automated analysis methods. Here we describe an approach to fully automate the analysis by integrating with data from the Allen Institute of Brain Science (AIBS), to provide precise assessment of the distribution and action of peptide-based pharmaceuticals in the brain. To illustrate this approach, we examined the acute central nervous system effects of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Peripherally administered liraglutide accessed the hypothalamus and brainstem, and led to activation in several brain regions of which most were intersected by projections from neurons in the lateral parabrachial nucleus. Collectively, we provide a rapid and unbiased analytical framework for LSFM data which enables quantification and exploration based on data from AIBS to support basic and translational discovery.

Highlights

Light Sheet Fluorescence Microscopy (LSFM) is an imaging system with high sensitivity, micrometer resolution, and short acquisition time enabling imaging of a whole mouse brain in less than one hour[1]
The Common Coordinate Framework version 3 (CCFv3) from Allen Institute for Brain Science (AIBS) was used as basis for constructing an integrated brain atlas to enable quantification and comparison of data regarding brain access, receptor location, neural activity, and brain connectivity
The atlas implementation combines user data from LSFM and histology, as well as connectivity maps downloaded from the AIBS data portal (Fig. 1a–c)

Summary

Introduction

Light Sheet Fluorescence Microscopy (LSFM) is an imaging system with high sensitivity, micrometer resolution, and short acquisition time enabling imaging of a whole mouse brain in less than one hour[1]. We present a pipeline with a similar scope of data integration by utilizing the multi-modality nature of the AIBS atlas, which besides an average mouse brain template based on tissue auto-fluorescence[3] contains an aligned histology-based template constructed from Nissl-stained brain sections[8]. This enables voxel-based alignment of 3D information from LSFM together with 2D information from histological techniques, such as in situ hybridization (ISH), for direct data comparison. The integrated brain atlas approach combined with easy-to-use visualization tools and quantification model was shown to enable high-throughput studies aiming to investigate peptides with brain mode-of-action

Methods

Results

Conclusion