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.
Abstract
The human hippocampus is a unique cortical structure central to brain function, plasticity, and disease. Unravelling its complex organization requires the integration of multiscale data, linking molecular features to mesoscale anatomy and macroscale functional patterns. Gene expression is a fundamental microscale phenotype, and its profiling can provide a reference description of how molecular features are distributed across the brain. Capitalizing on recent imaging-transcriptomic analyses, we introduce HippoGenes, a repository of fine-grained gene expression patterns across human hippocampal subregions. We leveraged spatial statistical models and hippocampal surface mapping to reconstruct dense transcriptomic maps from sparse post-mortem tissue samples of the Allen Human Brain Atlas, generating continuous expression estimates for thousands of genes aligned to a common surface-based coordinate system. We illustrate the utility of HippoGenes to (i) map medial-lateral and anterior-posterior transcriptomic gradients that align with subfield and tripartite subdivisions of the hippocampal formation, (ii) examine associations between gene expression and canonical microstructural and functional features of the hippocampus, and (iii) perform a molecular decoding of subregional alterations in neurological patients with hippocampal pathology. 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 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.
Michael S. Totty, Svitlana V. Bach, Madeline R. Valentine et al.· bioRxiv· 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
Gyrification of the cerebral cortex is essential for healthy brain development, and disruptions to this process lead to severe structural and functional abnormalities associated with long-term behavioural and psychiatric consequences. Basal radial glial cells (bRGC), residing in the expanded outer subventricular zone (oSVZ), are thought to drive gyrification. However, the transcriptional programs guiding this process remain poorly defined. We aimed to profile gene expression within the oSVZ of the developing ferret cortex, a species that displays postnatal gyrification, at two key stages of cortical folding, capturing its onset and progression. Discrete regions of the oSVZ were microdissected beneath the coronal gyrus and suprasylvian sulcus at the onset (P5, n = 5) and middle (P15, n = 5) of gyrification in the ferret. We performed RNA sequencing, differential expression analysis with gene ontology and pathway analyses with RT-qPCR validation of candidate genes. The results revealed spatially enriched gene sets associated with progenitor proliferation, self-renewal, and neurogenesis, as well as temporal transcriptional enrichment for axonogenesis and extracellular matrix regulation. RT-qPCR validated spatial and temporal expression differences, confirming consistent trends among some key folding-associated candidate genes. However, some genes (namely SOX9, AJAP1, and SEMA3D) showed inverse expression patterns compared to those detected by RNA-Seq and could not be considered validated. Together, these data define the molecular architecture of gyrification, providing a comprehensive transcriptional atlas of the oSVZ in the developing brain. Our findings advance understanding of how coordinated gene networks shape cortical folding, offering insights into the evolutional expansion of the mammalian brain.
M. Barresi, Alice Johnstone, Sebastian Quezada et al.· Brain Structure and Function· 0 citations
In Alzheimer’s disease (AD), misfolded proteins emerge across the entire brain in structured, yet not rigid, spatiotemporal patterns. Yet, a systematic bias of single-cell genomics toward sampling mostly cortical tissue limits our understanding of the whole-brain transcriptomic vulnerability to AD. Here, we develop a machine learning method to extrapolate local AD neuropathology signatures to the whole brain. By analyzing gene expression profiles of over two million cortical cells from 427 humans spanning the AD-pathology spectrum, we derive transcriptomic estimators of AD neuropathology. After extensive validations on datasets with known ground truth, we apply this framework to three million cells from 108 brain regions in the Siletti whole human brain atlas and derive an anticipated brain map of transcriptomic signatures indexing AD neuropathology. This interrogation of regions spanning the cortical, subcortical, and brainstem structures uncovers transcriptomic signatures associated with hyperphosphorylated tau in the medulla oblongata, dorsal raphe nucleus, and the tuberal and mammillary regions of the hypothalamus. At the cellular level, assessments of these signatures across 31 cell populations identify VGLUT1/2 expressing neurons, astrocytes, and microglia as key neuropathology-resembling populations. Within the hippocampus, pathology signatures surface in the rostral cornu ammonis (CA) subfields, particularly in the CA1 pyramidal neurons and dentate granule cells. β-amyloid-like signatures localize to the neocortex with laminar selectivity — most prominently in upper layer somatostatin+ intratelencephalic neurons (L2-L3), but also in deep layer intratelencephalic and corticothalamic neurons (L5-L6). Neocortical astrocytes and microglia exhibiting disease associated signatures similarly demonstrate a unique laminar preference. Together, this study provides the first whole human brain map of AD pathology-associated transcriptomic signals, and exposes cell type, region, and cortex layer specific vulnerabilities.
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
A "retrodictive" analysis of the cortex is presented that reconstructs the proliferation history of neural stem cells from a static snapshot of tissue, providing a developmentally grounded coordinate system for comparison across samples and is expected to be a foundational framework for 3D neuropathological analysis.
Tatsuya C. Murakami, Nathaniel Heintz· bioRxiv· 0 citations
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