Enabling multimodal whole-brain investigation for drug discovery

3D imaging modalities enable preclinical rodent brain imaging for investigating disease mechanisms and developing effective therapies. One of the major challenges inthe neuroimaging field has been the integration of data from in vivo magnetic resonance imaging (MRI) and ex vivo light sheet fluorescence microscopy (LSFM). Andalthough several computational tools are available for processing LSFM datasets, there is still room for improvement to enable automated, unbiased, and accurate analysis of LSFM-imaged whole brain volumes. This PhD project addressed these issues by developing a multimodal mouse brain atlas, a LSFM-based rat brain atlas and a voxel-wise statistical analysis pipeline to facilitate analysis and bridging of whole rodent brain datasets. The multimodal mouse brain atlas bridges MRI, LSFM and Allen Institute’s Common Coordinate Framework version 3. Additionally, it includes a skull-derived stereotaxic coordinate system, which connects every voxel in atlas templates to spatial positions in living mouse brains. The applicational value of established atlas resources and the analysis pipeline was demonstrated by characterizing and comparing LSFM-imaged brain activity patterns induced by six different body weight-lowering drugs. The screening study identified a set of brain regions, which may play a key role in appetite and body weight regulation by investigating shared and distinct features of drug-induced activation patterns. Outcomes of this PhD project allow high-throughput, unbiased investigation of complex processes as well as drug effects in whole rodent brains, and support anti-obesity drug discovery programs by identification of activity signatures in response to body weight-lowering drugs

Multimodal 3D Mouse Brain Atlas Framework with the Skull-Derived Coordinate System

Magnetic resonance imaging (MRI) and light-sheet fluorescence microscopy (LSFM) are technologies that enable non-disruptive 3-dimensional imaging of whole mouse brains. A combination of complementary information from both modalities is desirable for studying neuroscience in general, disease progression and drug efficacy. Although both technologies rely on atlas mapping for quantitative analyses, the translation of LSFM recorded data to MRI templates has been complicated by the morphological changes inflicted by tissue clearing and the enormous size of the raw data sets. Consequently, there is an unmet need for tools that will facilitate fast and accurate translation of LSFM recorded brains to in vivo, non-distorted templates. In this study, we have developed a bidirectional multimodal atlas framework that includes brain templates based on both imaging modalities, region delineations from the Allen’s Common Coordinate Framework, and a skull-derived stereotaxic coordinate system. The framework also provides algorithms for bidirectional transformation of results obtained using either MR or LSFM (iDISCO cleared) mouse brain imaging while the coordinate system enables users to easily assign in vivo coordinates across the different brain templates.</p