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Cellular and Molecular Bioengineering

Applications in Cellular and Molecular Bioengineering

Spatial multi-omic profiling of human hippocampus reveals region-specific alterations in major depressive disorder

Friday, October 13, 2023
5:00 PM – 5:15 PM PDT
Location: 322
Introduction:: The human hippocampus, a center of learning and memory, is a complex architecture with cellular and molecular heterogeneity. Previous work in single-nuclei studies provide a cell-type database in human hippocampus.[1-2] However, the missing information on cell states and their spatial relationship obscures the linkage between cellular function and the complex architecture of human hippocampus. To date, a spatial mapping of human hippocampus at a whole transcriptome level has not been reported. Our study provides the first spatial transcriptomic and epigenetic atlas of adult human hippocampus from 15 brains and identified high variability of RNA splicing observed in depression patients compared with controls.

Materials and Methods:: We performed DBiT-seq spatial mRNA and chromatin accessibility sequencing on 15 human hippocampi to capture the molecular complexity at 50 um resolution. Unsupervised clustering identified major hippocampal sub-regions, such as granule cell layer (GCL), molecular layer (ML), and Cornu Ammonis (CA_Pyr). We computed the RNA velocity using the state-of-art method scVelo [3] and identified Cornu Ammonis as the top dynamic region of RNA turnover. In addition, psychiatrically healthy brains were compared with brains from major depressive disorder (MDD) patients to identify pathogenic genes and altered biological pathways.

Results, Conclusions, and Discussions:: We present a spatial multi-omic atlas of adult human hippocampus based on transcriptomic and epigenomic sequencing of 15 hippocampi from 8 healthy donors and 7 MDD patients. De-convoluted cell type maps of each hippocampal sub-field were constructed. We observed surprisingly variable splicing activity in MDD vs. heathy control. Analysis of RNA velocity suggested that cell-type specific transcriptomic instability may be characteristic of MDD and revealed a high inter-patient heterogeneity of splicing dynamics particularly in the Cornu Ammonis pyramidal neurons.

We demonstrated the applicability and promise of spatial transcriptomics for the study of molecular neuropathology. RNA velocity, a powerful indicator of the cell states, revealed the altered cell dynamics in the Cornu Ammonis region of the MDD patients.


Acknowledgements (Optional): :

References (Optional): : [1] F. Ayhan, A. Kulkarni, S. Berto, K. Sivaprakasam, C. Douglas, B. C. Lega, G. Konopka, Neuron 2021, 109, 2091.
[2] D. Franjic, M. Skarica, S. Ma, J. I. Arellano, A. T. N. Tebbenkamp, J. Choi, C. Xu, Q. Li, Y. M. Morozov, D. Andrijevic, Z. Vrselja, A. Spajic, G. Santpere, M. Li, S. Zhang, Y. Liu, J. Spurrier, L. Zhang, I. Gudelj, L. Rapan, H. Takahashi, A. Huttner, R. Fan, S. M. Strittmatter, A. M. M. Sousa, P. Rakic, N. Sestan, Neuron 2021, DOI: 10.1016/j.neuron.2021.10.036.
[3] V. Bergen, M. Lange, S. Peidli, F. A. Wolf, F. J. Theis, Nat Biotech 2020, DOI: 10.1038/s41587-020-0591-31.