Abstract
The brain is composed of diverse neuronal and non-neuronal cell types with complex regional connectivity patterns that create the anatomical infrastructure underlying cognition. Remarkable advances in neuroscience techniques enable labeling and imaging of these individual cell types and their interactions throughout intact mammalian brains at a cellular resolution allowing neuroscientists to examine microscopic details in macroscopic brain circuits. Nevertheless, implementing these tools is fraught with many technical and analytical challenges with a need for high-level data analysis. Here we review key technical considerations for implementing a brain mapping pipeline using the mouse brain as a primary model system. Specifically, we provide practical details for choosing methods including cell type specific labeling, sample preparation (e.g., tissue clearing), microscopy modalities, image processing, and data analysis (e.g., image registration to standard atlases). We also highlight the need to develop better 3D atlases with standardized anatomical labels and nomenclature across species and developmental time points to extend the mapping to other species including humans and to facilitate data sharing, confederation, and integrative analysis. In summary, this review provides key elements and currently available resources to consider while developing and implementing high-resolution mapping methods.
Highlights
Macro-circuits across the brain integrate information from regional micro-circuits to process external stimuli, evaluate internal state, and generate behavior
Recent single cell transcriptomic approaches combined with other physiological analyses unveiled that more than 100 different neuronal cell types exist in the mouse isocortex with distinct connectivity, physiology, and molecular characteristics
Adeno-associated virus (AAV) with a recombinase-dependent reporter can be injected into the target area of a cell-type specific Cre and/or Flp driver animal (Figure 2C)
Summary
Macro-circuits across the brain integrate information from regional micro-circuits to process external stimuli, evaluate internal state, and generate behavior (e.g., motor action). Many neuroimaging tools such as magnetic resonance imaging (MRI) can provide volumetric imaging, but they don’t offer sufficient resolution to image individual cells and lack the ability to distinguish individual cell types Mesoscale imaging bridges these two scales by combining high-resolution 3D imaging and computational analysis to allow visualization and quantification of axons, cell nuclei, processes, and even synapses in intact biological samples (Odgaard et al, 1990; Dodt et al, 2007; Mayerich et al, 2008; Li et al, 2010; Zheng et al, 2019; Ueda et al, 2020a,b). Similar mapping approaches are possible in other species such as the non-human primate (NHP) as well as human brains (Woodward et al, 2020; Rapan et al, 2021; Shapson-Coe et al, 2021)
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