A spatial transcriptomic atlas of the human amygdala from nine neurotypical donors provides a foundational resource and framework for accelerating cross-species comparisons and human disease-focused investigations.
Abstract
The amygdala is a central hub for emotional learning that is dysregulated across numerous psychiatric disorders, yet its molecular architecture in humans remains poorly defined. We here present a spatial transcriptomic atlas of the human amygdala from nine neurotypical donors. Integrating Visium, Xenium, and VisiumHD technologies, we profiled over 1.1 million cells across 13 spatial domains spanning the basolateral complex, central, medial, and cortical nuclei, as well as the intercalated islands, each defined by distinct marker genes and gene co-expression networks. By integrating snRNA-seq reference atlases, we found that each subdivision of the basolateral subnucleus contains distinct excitatory neuron classes. We additionally found three transcriptionally distinct populations of intercalated neuron types, two of which form spatially distinct islands neighboring the basolateral complex, and were able to refine cell type diversity across the central nucleus and related amygdalostriatal transition areas. Finally, we localized psychiatric genetic risk across the amygdala, revealing both broad neuronal enrichment and subnuclear specificity. Together, this atlas provides a foundational resource and framework for accelerating cross-species comparisons and human disease-focused investigations.
HippoGenes provides a framework for exploring the molecular organization of the hippocampus, opening avenues for multiscale integration in health and disease, and is openly available on https://hippogenes.readthedocs.io.
A. Ngo, Sara Larivière, J. Royer et al.· bioRxiv· 0 citations
The striatum is critical for decision-making, movement, and reward processing, functions achieved through subregional cellular and molecular specialization. Striatal cell types and subregions are differentially implicated in neurodegenerative and neuropsychiatric disorders, but the mechanisms underlying these vulnerabilities are poorly understood. Using single-nucleus RNA sequencing across 109 human and 22 mouse samples spanning dorsal and ventral striatum, we provide a comprehensive atlas of subregional neuronal specialization. We define rare neuronal subpopulations and transcriptional gradients along the dorsolateral-ventromedial axis with notable differences between species, suggesting divergent pharmacological targets, connectivity, and disease mechanisms. Integration with genome-wide association and pharmacological studies identifies human-enriched sites of opioid receptor expression and ventral-biased chronic antipsychotic action. Lastly, paired single-cell transcriptomic and somatic trinucleotide repeat expansion measurements identify differences in subregion and neuronal subtype vulnerability in Huntington's disease. Our findings lay the foundation for understanding how striatal cell types and subregions contribute to brain function and neurological disorders.
Raleigh M. Linville, Benjamin T. James, K. Galani et al.· Cell· 0 citations
The hippocampus (HPC) and medial entorhinal cortex (MEC) are essential for learning, memory, and spatial cognition, and both exhibit dorsoventral (longitudinal) organization across mammalian species. While prior studies have highlighted functional differences along this axis, the molecular basis and cross-species conservation of these differences remain poorly understood. Here, we employed spatial transcriptomics to generate a comprehensive molecular atlas of HPC and MEC in five species—human, tree shrew, mouse, canine, and pig—standardizing the dorsoventral axis for cross-species comparison. Using support vector machine (SVM) models, we identified high-weight genes predictive of dorsoventral identity and revealed conserved functional patterns: dorsal HPC was enriched for cytoskeletal and synaptic pathways, while ventral HPC favored nucleotide and energy metabolism. In the MEC, dorsal regions were enriched for calcium transport and lipid metabolism, whereas ventral regions were associated with calcium homeostasis and amyloid regulation. Species-specific SVM models uncovered dramatic divergence, leading us to propose the ancestral confinement theory, suggesting that conserved dorsoventral features are maintained within an evolutionary framework that permits species-specific adaptations. To link molecular patterns with cell types, we conducted single-nucleus RNA sequencing of tree shrew HPC and MEC and integrated data from other species. Deconvolution analysis showed species-specific GABAergic neuron distributions along the axis, with notable dorsal enrichment in human and ventral enrichment in other species. Together, our findings provide a cross-species molecular framework of HPC and MEC organization, revealing both conserved and species-specific dorsoventral programs underlying brain function and evolution.
Sihui Cheng, Qirun Wang, Ye Feng et al.· bioRxiv· 0 citations
The central amygdala (CeA) orchestrates defensive behaviors, pain processing, and stress responses, yet how its molecularly defined neuronal subtypes are embedded in brain-wide circuits remains unclear. Here, we reconstructed the brain-wide input and output architecture of three neuronal subtypes, CeASst, CeAPkc-δ, and CeACrh neurons, at single-cell resolution in male mice. Single-cell reconstruction revealed various projection-defined classes within each molecular-defined subtype, ranging from locally restricted neurons to broadly broadcasting neurons that coinnervate hypothalamic, midbrain, and brainstem. CeA outputs exhibit subtype-specific hemispheric asymmetry, providing an anatomical substrate for functional lateralization of CeA circuits. Coprojection analysis showed segregated and convergent CeA output pathways across midbrain and brainstem structures, supporting functional heterogeneity in the selection of appropriate defensive behaviors. Mapping of the input of these neurons further uncovered segregated and spatially organized upstream networks. Cortical projection neurons, particularly from the insular cortex, sent lateralized projections to distinct CeA subregions. Joint analysis of cortical and CeA projection architectures revealed structural signatures of both serial and parallel coordination. Taken together, these findings demonstrate a multilevel, subtype-specific, and lateralized architecture linking molecular identity to brain-wide CeA connectivity.
Lung-Chuang Wang, Wei Song, Xu Chen et al.· Journal of Neuroscience· 0 citations
A comprehensive cerebrovascular cell atlas encompassing 314,535 transcriptomes is constructed that captures the arteriovenous axis and defines consensus cell states and identifies ensemble-specific susceptibilities and candidate therapeutic targets across neurological diseases, including small vessel disease and stroke.
Jerry C. Wang, Damian A Sanchez, Santhosh Arul et al.· Cell· 1 citation
The serotonin system innervates nearly the entire brain to support diverse functions, and its dysfunction is implicated in multiple psychiatric disorders. Although recent studies suggested that this anatomically diffuse system supports differentiated rather than uniform modulation, its overall organization is unclear. Here, using systematic whole-brain axon tracing and integrated analyses, we show that the serotonin projectome is organized by functional relatedness rather than physical proximity of its targets. Dorsal and median raphe serotonin neurons partition into five projectomic groups, each preferentially innervating the hippocampus, basal ganglia, cortex, medial interbrain, or brainstem/lateral thalamus, with within-group structure ranging from discrete subgroups to continuous variation. Spatial transcriptomic analyses reveal that each projectomic group corresponds to a distinct combination of transcriptomic clusters, with transcriptome and somatic position jointly predicting projectomic identity. Projection-specific serotonin depletion produces dissociable behavioral phenotypes. Together, projectomic identity emerges as a central axis linking axon collateralization, molecular diversity, and behavioral function.
