Multimodal Gradient Mapping of Rodent Hippocampus

The hippocampus plays a central role in supporting our coherent and enduring sense of self and our place in the world. Understanding its functional organisation is central to understanding this complex role. Previous studies suggest function varies along a long hippocampal axis, but there is disagreement about the presence of sharp discontinuities or gradual change along that axis. Other open questions relate to the underlying drivers of this variation and the conservation of organisational principles across species. Here, we delineate the primary organisational principles underlying patterns of hippocampal functional connectivity (FC) in the mouse using gradient analysis on resting state fMRI data. We further applied gradient analysis to mouse gene co-expression data to examine the relationship between variation in genomic anatomy and functional organisation. Two principal FC gradients along a hippocampal axis were revealed. The principal gradient exhibited a sharp discontinuity that divided the hippocampus into dorsal and ventral compartments. The second, more continuous, gradient followed the long axis of the ventral compartment. Dorsal regions were more strongly connected to areas involved in spatial navigation while ventral regions were more strongly connected to areas involved in emotion, recapitulating patterns seen in humans. In contrast, gene co-expression gradients showed a more segregated and discrete organisation. Our findings suggest that hippocampal functional organisation exhibits both sharp and gradual transitions and that hippocampal genomic anatomy exerts a subtle influence on this organisation.

Spatial transcriptome sequencing revealed spatial trajectory in the Non-Small Cell Lung Carcinoma

Deepening understanding in the heterogeneity of tumors is critical for clinical treatment. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal lung cancer using the spatial transcriptomics (ST) technology. We identified gene expression gradients in stroma adjacent to tumor regions that allow for re-understanding of the tumor micro-environment. The establishment of these profiles was the first step towards an unbiased view of lung cancer and can serve as a dictionary for future studies. Tumor subclones were detected by ST technology in our research, while we contrast the EMT ability among in subclones which inferred the possible trajectory of tumor metastasis and invasion, which was confirmed by constructing the pseudo-time model of spatial transition within subclones. Together, these results uncovered lung cancer spatial heterogeneity, highlight potential tumor micro-environment differences and spatial evolution trajectory, and served as a resource for further investigation of tumor microenvironment.

Modelling the emergence of whisker barrels

Brain development relies on an interplay between genetic specification and self-organization. Striking examples of this relationship can be found in the somatosensory brainstem, thalamus, and cortex of rats and mice, where the arrangement of the facial whiskers is preserved in the arrangement of cell aggregates to form precise somatotopic maps. We show in simulation how realistic whisker maps can self-organize, by assuming that information is exchanged between adjacent cells only, under the guidance of gene expression gradients. The resulting model provides a simple account of how patterns of gene expression can constrain spontaneous pattern formation to faithfully reproduce functional maps in subsequent brain structures.

Extensive and spatially variable within-cell-type heterogeneity across the basolateral amygdala

The basolateral amygdala complex (BLA), extensively connected with both local amygdalar nuclei as well as long-range circuits, is involved in a diverse array of functional roles. Understanding the mechanisms of such functional diversity will be greatly informed by understanding the cell-type-specific landscape of the BLA. Here, beginning with single-cell RNA sequencing, we identified both discrete and graded continuous gene-expression differences within the mouse BLA. Via in situ hybridization, we next mapped this discrete transcriptomic heterogeneity onto a sharp spatial border between the basal and lateral amygdala nuclei, and identified continuous spatial gene-expression gradients within each of these regions. These discrete and continuous spatial transformations of transcriptomic cell-type identity were recapitulated by local morphology as well as long-range connectivity. Thus, BLA excitatory neurons are a highly heterogenous collection of neurons that spatially covary in molecular, cellular, and circuit properties. This heterogeneity likely drives pronounced spatial variation in BLA computation and function.

Atypical genomic patterning of the cerebral cortex in autism with poor early language outcome

Cortical regional identities develop through anterior-posterior (A-P) and dorsal-ventral (D-V) prenatal genomic patterning gradients. Here we find that A-P and D-V genomic patterning of cortical surface area (SA) and thickness (CT) is intact in typically developing and autistic toddlers with good language outcome, but is absent in autistic toddlers with poor early language outcome. Genes driving this effect are prominent in midgestational A-P and D-V gene expression gradients and prenatal cell types driving SA and CT variation (e.g., progenitor cells versus excitatory neurons). These genes are also important for vocal learning, human-specific evolution, and prenatal co-expression networks enriched for high-penetrance autism risk genes. Autism with poor early language outcome may be linked to atypical genomic cortical patterning starting in prenatal periods and which impacts later development of regional functional specialization and circuit formation.One Sentence SummaryGenomic patterning of the cortex is atypical in autistic toddlers with poor early language outcome.

Modelling the emergence of whisker barrels

Brain development relies on an interplay between genetic specification and self-organization. Striking examples of this relationship can be found in the somatosensory brainstem, thalamus, and cortex of rats and mice, where the arrangement of the facial whiskers is preserved in the arrangement of cell aggregates to form precise somatotopic maps. We show in simulation how realistic whisker maps can self-organize, by assuming that information is exchanged between adjacent cells only, under the guidance of gene expression gradients. The resulting model provides a simple account of how patterns of gene expression can constrain spontaneous pattern formation to faithfully reproduce functional maps in subsequent brain structures.

Innovations in Primate Interneuron Repertoire

ABSTRACTPrimates and rodents, which descended from a common ancestor more than 90 million years ago, exhibit profound differences in behavior and cognitive capacity. Modifications, specializations, and innovations to brain cell types may have occurred along each lineage. We used Drop-seq to profile RNA expression in more than 184,000 individual telencephalic interneurons from humans, macaques, marmosets, and mice. Conserved interneuron types varied significantly in abundance and RNA expression between mice and primates, but varied much more modestly among primates. In adult primates, the expression patterns of dozens of genes exhibited spatial expression gradients among neocortical interneurons, suggesting that adult neocortical interneurons are imprinted by their local cortical context. In addition, we found that an interneuron type previously associated with the mouse hippocampus—the “ivy cell”, which has neurogliaform characteristics—has become abundant across the neocortex of humans, macaques, and marmosets. The most striking innovation was subcortical: we identified an abundant striatal interneuron type in primates that had no molecularly homologous cell population in mouse striatum, cortex, thalamus, or hippocampus. These interneurons, which expressed a unique combination of transcription factors, receptors, and neuropeptides, including the neuropeptide TAC3, constituted almost 30% of striatal interneurons in marmosets and humans. Understanding how gene and cell-type attributes changed or persisted over the evolutionary divergence of primates and rodents will guide the choice of models for human brain disorders and mutations and help to identify the cellular substrates of expanded cognition in humans and other primates.

Human visual cortex is organized along two genetically opposed hierarchical gradients with unique developmental and evolutionary origins

Human visual cortex is organized with striking consistency across individuals. While recent findings demonstrate an unexpected coupling between functional and cytoarchitectonic regions relative to the folding of human visual cortex, a unifying principle linking these anatomical and functional features of cortex remains elusive. To fill this gap in knowledge, we combined independent and ground truth measurements of human cytoarchitectonic regions and genetic tissue characterization within the visual processing hierarchy. Using a data-driven approach, we examined if differential gene expression among cortical areas could explain the organization of the visual processing hierarchy into early, middle, and late processing stages. This approach revealed that the visual processing hierarchy is explained by two opposing gene expression gradients: one that contains a series of genes with expression magnitudes that ascend from the first processing stage (e.g. area hOc1, or V1) to the last processing stage (e.g. area FG4) and another that contains a separate series of genes that show a descending gradient. In the living human brain, each of these gradients correlates strongly with anatomical variations along the visual hierarchy such as the thickness or myelination of cortex. We further reveal that these genetic gradients emerge along unique trajectories in human development: the ascending gradient is present at 10- 12 gestational weeks, while the descendent gradient emerges later (19-24 gestational weeks). Interestingly, it is not until early childhood (before 5 years of age) that the two expression gradients achieve their adult-like mean expression values. Finally, additional analyses in non-human primates (NHP) reveal the surprising finding that only the ascending, but not the descending, expression gradient is evolutionarily conserved. These findings create one of the first models bridging macroscopic features of human cytoarchitectonic areas in visual cortex with microscopic features of cellular organization and genetic expression, revealing that the hierarchy of human visual cortex, its cortical folding, and the cytoarchitecture underlying its computations, can be described by a sparse subset (~200) of genes, roughly one-third of which are not shared with NHP. These findings help pinpoint the genes contributing to both healthy cortical development and the cortical biology distinguishing humans from other primates, establishing essential groundwork for understanding future work linking genetic mutations with the function and development of the human brain.