A method to estimate the cellular composition of the mouse brain from heterogeneous datasets

Abstract

The mouse brain contains a rich diversity of inhibitory interneuron types that have been characterized by their patterns of gene expression. However, the distribution of these cell types across the mouse brain is still incomplete. We developed a computational method to establish a consensus on the estimate of the densities of different interneuron types across the mouse brain. This method allows the unbiased integration of diverse and disparate datasets into a framework to predict interneuron densities for uncharted brain regions. We constrained our estimates based on previously computed brain-wide neuron density data, gene expression from in situ hybridization image stacks together with a wide range of values reported in the literature. Using optimization, we derived coherent estimates of cell densities for the different interneuron types. We estimated that 20.3% of all neurons in the mouse brain are inhibitory. Among all inhibitory neurons, 18% predominantly express parvalbumin (PV), 16% express somatostatin (SST), 3% express vasoactive intestinal peptide (VIP), and the remainder 63% belong to the residual GABAergic population. Our pipeline is extensible, allowing new cell types or data to be integrated as they become available. The data, algorithms, software, and results of this pipeline are publicly available and update the Blue Brain Cell Atlas. We find that our density estimations improve as more literature values are integrated. This work therefore leverages the research community to collectively converge on the numbers of each cell type in each brain region.Author summaryObtaining a global understanding of the cellular composition of the brain is a very complex task, not only because of the great variability that exists between reports of similar counts but also because of the numerous brain regions and cell types that make up the brain. Previously, we presented a model of a cell atlas, which provided an estimate of the densities of neurons, glia and their subtypes for each region in the mouse brain. Here, we describe an extension of this model to include more inhibitory neuron types. We collected estimates of inhibitory neuron counts from literature and built a framework to combine them into a consistent cell atlas. Using brain slice images, we also estimated inhibitory neuron density in regions where no literature data are available. We estimated that in the mouse brain 20.3% of all neurons are inhibitory. Among all inhibitory neurons, 18% predominantly express parvalbumin (PV), 16% express somatostatin (SST), 3% express vasoactive intestinal peptide (VIP), and the remainder 63% belong to the residual GABAergic population Our approach can be further extended to any other cell type and provides a resource to build tissue-level models of the rodent brain.

Efficient image analysis for large-scale next generation histopathology using pAPRica

“…After atlas registration, the density of PV+ neurons was measured in brain regions of interest. The cell distribution was found to be similar to previous studies 10 (Fig. 1m).…”

“…k, Horizontal and l , coronal views of the brain autofluorescence channel overlaid with the Allen Brain Atlas region boundaries after registration. m , Comparison between the number of segmented PV+ neurons found in our dataset with a previously published reference 10 . For each brain region, the PV+ neuron density is overlaid as a color map (from purple for low density to bright orange for high density) on the acquired data.…”

Synaptic wiring motifs in posterior parietal cortex support decision-making

“…2b, E-to-E = 0.4±0.1%, E-to-I: = 1.7±0.1%, p<1e-14 Mann-Whitney U-test). This was largely due to preferential targeting of inhibitory neurons: 67% of excitatory synapses were E-to-I even though inhibitory neurons make up only about 20% of local neurons 41 (Ext. Data Fig.…”

“… (a) PPC excitatory neurons target inhibitory partners at higher rates than inhibitory (excitatory: 66±2%, n=59 neurons, inhibitory: 38±5%, n=11, p < 10 −4 , Mann Whitney U test). Dotted line – estimated overall proportion of inhibitory neurons (∼20%) 41 . (b) Normalized synapse frequency plotted as a function of selectivity similarity index for I-to-E connections in PPC, calculated using functional data from early (10-8 days before sacrifice), middle (7-4 days before), and late (3-0 days before) sessions (early: n=93, middle: n=107, late: n=111).…”

Parvalbumin-Positive Interneurons Regulate Cortical Sensory Plasticity in Adulthood and Development Through Shared Mechanisms

“…cPVins represent an estimated 5-20% of cells in the brain, and up 40-50% of the inhibitory population, based on developmental progenitor and tracing studies (Tamamaki et al, 2003;Butt et al, 2005;Rudy et al, 2011;Rodarie et al, 2021). Despite similar genetic profiles (Tasic, 2018), and gross numbers of afferent thalamic inputs (Pouchelon et al, 2021) across cortical IN subtypes, individual cPVins have unique cellular physiological characteristics that enable them to locally shape sensory responses.…”