Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism - PubMed (original) (raw)

. 2017 Oct 5;171(2):456-469.e22.

doi: 10.1016/j.cell.2017.09.020.

Guangyu Robert Yang 2, Kith Pradhan 3, Kannan Umadevi Venkataraju 3, Mihail Bota 3, Luis Carlos García Del Molino 2, Greg Fitzgerald 3, Keerthi Ram 4, Miao He 5, Jesse Maurica Levine 6, Partha Mitra 3, Z Josh Huang 3, Xiao-Jing Wang 7, Pavel Osten 8

Affiliations

Brain-wide Maps Reveal Stereotyped Cell-Type-Based Cortical Architecture and Subcortical Sexual Dimorphism

Yongsoo Kim et al. Cell. 2017.

Abstract

The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitative brain-wide (qBrain) mapping platform to document the stereotyped distributions of mainly inhibitory cell types. We discover an unexpected cortical organizing principle: sensory-motor areas are dominated by output-modulating parvalbumin-positive interneurons, whereas association, including frontal, areas are dominated by input-modulating somatostatin-positive interneurons. Furthermore, we identify local cell type distributions with more cells in the female brain in 10 out of 11 sexually dimorphic subcortical areas, in contrast to the overall larger brains in males. The qBrain resource can be further mined to link stereotyped aspects of neuronal distributions to known and unknown functions of diverse brain regions.

Keywords: Cell type; brain; cortex; inhibition; sexual dimorphism.

Copyright © 2017 Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Quantitative cell type mapping in the mouse brain

(A) Genetic strategy to label brain cell types by Cre and Cre and Flp drivers. Top: the cell type-specific Cre and Flp mouse lines; bottom: the fluorescent protein-based reporter lines. (B) Reconstructed SST-Cre:H2B-GFP mouse brain imaged by STPT (B1) and the detected SST+ cell distribution (B2). Each brain is registered to a reference STP (RSTP) brain aligned with the common coordinate framework Allen Brain atlas (B3) for anatomical segmentation of the whole-brain cell type distribution. (C) Cell densities per mm3 of each of the seven cell types analyzed in our study are visualized as whole brain flatmaps (see Figure S1 for a high resolution flatmap; complete cell counts and cell densities are given in Tables S1 and S3).

Figure 2

Figure 2. Uneven distribution of the three major interneurons in the isocortex

(A) Unbiased voxel-based quantitative mapping. The first three columns show the PV+, SST+, and VIP+, and the last column the combined signals overlaid on the RSTP brain with anatomical segmentation information (see also Movie S1). The heatmap represents number of cells per voxel (a sphere of 100µm diameter). The A/P bregma position is shown in the first column. (Tables Sl–3 list the full anatomical names). (B–E) Cell density mapping using a cortical flatmap (B). The heatmap displays of cell density per mm3 for the VIP+ (C), PV+ (D), and SST+ (E) cell populations. Note the low density of PV+ and high density of SST+ in the medial frontal (blue arrow) and lateral association cortices (orange arrow). (F –G) Cell density plots (F) and relative distribution (G) of the three interneuron cell types across anatomical regions of the isocortex arranged in five subnetworks based on their anatomical connectivity (Zingg et al., 2014) (see also Tables S3 for complete dataset). The values in (F) = mean ± standard deviation.

Figure 3

Figure 3. Cell type-specific laminar cortical distribution

(A) Examples of the seven cell types in the six-layer primary auditory (top panel) and five-layer dorsal anterior cingulate (bottom panel) cortex (full datasets are deposited at

http://mouse.brainarchitecture.org/cellcounts/ost/

). (B–C) Relative cortical layer cell densities from the primary auditory (B) and dorsal anterior cingulate (C) cortices, with each cell type color-coded as shown on the right (the values = mean ± standard deviation). (D–E) Average relative cortical layer cell densities from all 6-layer (D) and 5-layer (E) cortical areas, shown with the same figure composition as in (B–C) (the values = mean ± standard deviation). Note the stereotypic layer distribution of the interneuron subtypes across the mouse isocortex.

Figure 4

Figure 4. Cortical area hierarchy in L2/3 PV+ to SST+ density ratios

(A) Cortical areas are segregated in space of L2/3 PV+ and SST+ density according to their cortical subnetworks (color coded). (B) Decision boundaries of linear discriminant analysis classifiers using, from left to right, PV+/SST+, PV+/VIP+, or SST+/VIP+ cell densities. (C) Cross-validated classifier performances on left-one-out data, when different combinations of density information are used. Gray area indicates the 95% confidence interval of classifier performances on shuffled data. (D) Cortical areas ranked by their PV+/SST+ cell density ratios.

Figure 5

Figure 5. Modeling response properties of local circuits while varying cell densities

(A) Cortical circuit model with an excitatory (E) and three inhibitory populations (PV, SST, and VIP) (Pfeffer et al., 2013). Output weights of an inhibitory population are proportional to the density of that population. (B,C) Comparing cell densities (B) and local circuit responses (C) in areas SSp-bfd and ILA. (C) From top to bottom: E population activity, PV-to-E, SST-to-E, VIP-to-SST, and E-to-E currents in response to external inputs driving the PV population. Spontaneous activities are kept the same across areas. (D,E) Same comparisons as in (B,C), for areas AUDpo and RSPv. (F–H) Responses of E population activity (F) and PV-to-E current (G) depend on both PV+ and SST+ cell densities. (H) Maps of circuit responses overlaid with the distribution of cortical areas in the PV+/SST+ density plane. (I) Increasing SST+ density strengthens the PV-SST-PV effective disinhibitory loop, leading to a stronger PV-to-E current response.

Figure 6

Figure 6. Subcortical distribution patterns of seven cell types

(A) Virtual density overlay reveals distinct anatomical distribution of each cell type. For example, enriched expression of SST neurons in the central amygdala is extended to more anterior ventral part of caudate putamen (light blue arrows). Some area is exclusively occupied by one cell type (PV in GPe, STN, SN, white arrow). PV and SST neurons showed dorsal and ventral expression in the GPi (white arrow head) and in the ZI (purple arrow head). PV neurons are highly expressed in basal ganglia (white arrows). Numbers represent A/P bregma. See also Movie S1. (B) High resolution images to show topographical separation of PV and SST neurons expression in GPi and ZI. (C) Genetic intersection approach reveals specific expression from SST subtypes in medial amygdala. Numbers represent A/P bregma (see also Movie S2).

Figure 7

Figure 7. Sexually dimorphic expression of SST+ and VIP+ neurons

(A–D) Examples of sexually dimorphic regions (A–B) SST showed higher number of cells in females than males in medial preoptic nucleus (MPN) and posteroventral medial amygdala (MEApv), and lower number in posterodorsal preoptic nucleus (PD, red arrow). (C–D) VIP showed higher number of cells in the female than males in MPN and dorsal raphe (DR). See Table S4 for the complete list including the cell counting.

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