Abstract
The claustrum is a functionally and structurally complex brain region, whose very spatial extent remains debated. Histochemical-based approaches typically treat the claustrum as a relatively narrow anatomical region that primarily projects to the neocortex, whereas circuit-based approaches can suggest a broader claustrum region containing projections to the neocortex and other regions. Here, in the mouse, we took a bottom-up and cell-type-specific approach to complement and possibly unite these seemingly disparate conclusions. Using single-cell RNA-sequencing, we found that the claustrum comprises two excitatory neuron subtypes that are differentiable from the surrounding cortex. Multicolor retrograde tracing in conjunction with 12-channel multiplexed in situ hybridization revealed a core-shell spatial arrangement of these subtypes, as well as differential downstream targets. Thus, the claustrum comprises excitatory neuron subtypes with distinct molecular and projection properties, whose spatial patterns reflect the narrower and broader claustral extents debated in previous research. This subtype-specific heterogeneity likely shapes the functional complexity of the claustrum.
Highlights
The claustrum has been implicated in a variety of functions and behaviors, including attention (Atlan et al, 2018; Goll et al, 2015; Smith et al, 2019), impulsivity (Liu et al, 2019), sleep (Narikiyo et al, 2020; Norimoto et al, 2020; Renouard et al, 2015), and the integration of information to support consciousness (Crick and Koch, 2005; Smythies et al, 2012)
From claustral microdissections from four mice, we manually harvested 1112 cells based on a combination of unbiased blind selection of cells and selection of specific labeled projections
After library preparation, sequencing, and filtering, we retained a total of 1011 excitatory neurons for analysis (n = 478 cells blindly selected; n = 286 and 247 cells projecting to the lateral entorhinal cortex (LEC) and retrosplenial cortex (RSC), respectively)
Summary
The claustrum has been implicated in a variety of functions and behaviors, including attention (Atlan et al, 2018; Goll et al, 2015; Smith et al, 2019), impulsivity (Liu et al, 2019), sleep (Narikiyo et al, 2020; Norimoto et al, 2020; Renouard et al, 2015), and the integration of information to support consciousness (Crick and Koch, 2005; Smythies et al, 2012). To determine the mechanistic contributions of the claustrum to these putative functions, it is essential to understand both the intrinsic organization of claustrum neurons, as well as how this organization relates to connectivity and function (Edelstein and Denaro, 2004). Such an interpretation is challenged by the fact that even the precise anatomical boundaries of the claustrum are a matter of debate (Dillingham et al, 2019; Smith et al, 2019). To facilitate future research analyzing claustral cell-type- specific structure and function, data and analysis tools from this study are available via our interactive web portal (http://scrnaseq.janelia.org/claustrum)
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