This study performed an integrated multimodal analysis of the adult human hippocampus in major depressive disorder (MDD) versus neurotypical controls. The authors combined single-nucleus RNA sequencing, assay for transposase-accessible chromatin sequencing (ATAC), spatial transcriptomics and regional proteomics to characterize cellular states and regulatory programs. After quality control, 495,037 nuclei from 11 MDD and 19 control samples were retained for analysis; initial sampling included additional subjects and technical replicates that were modelled as covariates. Batch-, sample- and donor-correction methods were applied before downstream analyses, and integration of RNA and ATAC modalities was performed using a weighted nearest neighbor strategy. Spatial data (Visium) and in situ hybridization (Xenium) were anchored to the single-nucleus reference to provide anatomical localization of clusters.
The combined transcriptomic and chromatin-accessibility data identified a neurogenic lineage within the adult human hippocampal subgranular zone (SGZ). Marker gene expression and multimodal clustering supported the presence of proliferative and differentiating progenitor states consistent with an ongoing neurogenic trajectory in adult hippocampus. Spatial integration localized these neurogenic states within hippocampal subregions, enabling mapping of lineage progression in anatomical context.
Comparative analyses between nonmedicated individuals with MDD and controls provided evidence for a stalled neurogenic process in MDD. The stalled phenotype was associated with altered transcriptional regulation across developmental stages of the lineage, increased signals consistent with stress-related cellular reprogramming, and engagement of interferon signaling pathways. These changes were observed across the defined neurogenic stages rather than being restricted to a single state, suggesting a broad disruption of lineage progression in MDD.
The dataset enabled cell-type- and hippocampal-subfield-specific interrogation of gene expression and chromatin accessibility. Excitatory and inhibitory neuron populations both exhibited dysregulation of transcription factor networks predicted to influence cell states. Epigenetic signatures derived from ATAC data supported transcriptional perturbations and implicated regulatory mechanisms in MDD-related changes. The authors also report dysregulated long noncoding RNAs across cell types, indicating multi-level gene regulatory disruption in the MDD hippocampus.
Analyses focused on the hippocampal trisynaptic memory circuit—dentate gyrus (DG) and cornu ammonis (CA) regions—revealed disrupted excitatory–inhibitory balance, impaired synaptic plasticity and altered neurotransmission in MDD. These circuit-level abnormalities were linked to altered transcriptional and epigenetic regulation within excitatory and inhibitory neuronal populations. Because hippocampal pattern separation and certain forms of memory depend on DG neurogenesis and circuit integrity, the authors relate the observed cellular and molecular deficits to known cognitive features of MDD, such as negative memory bias.
Across all examined cell types, common maladaptive signatures emerged in MDD samples. These included markers of cellular stress and impaired intracellular trafficking, signatures of serotonergic and glutamatergic dysfunction, reduced metabolic capacity, and evidence of immune activation and neuroinflammation. Interferon signaling was specifically highlighted across developmental stages of the neurogenic lineage. The authors note that genetic and epigenetic regulation of gene expression appears to contribute to these disease-associated signatures.
The multimodal atlas and findings provide a molecular framework linking impaired adult hippocampal neurogenesis and hippocampal circuit dysfunction to hippocampus-dependent cognitive symptoms in MDD. The study indicates overlapping pathogenetic mechanisms between MDD and autoimmune, neurodevelopmental and neurodegenerative disorders, based on shared transcriptional and immune-related signatures. The authors suggest that the identified regulatory pathways and cellular states could inform future therapeutic target discovery. Specific therapeutic targets or interventional data were not provided in the supplied excerpt.
Notes on methods and scope
The reported work is based on nonmedicated individuals with MDD and neurotypical controls; multimodal single-nucleus and spatial approaches were used to integrate transcriptomic, chromatin accessibility and proteomic data. Details on exact proteomic findings, statistical effect sizes, full lists of differentially expressed genes or chromatin peaks, and subject-level demographic or clinical covariates are described in the full article and supplementary materials but were not included in the provided source excerpt.
Conclusions
This study supports the presence of an adult human hippocampal neurogenic lineage and provides multimodal evidence for dysregulated neurogenesis and widespread transcriptional and epigenetic alterations in MDD. Dysregulated neurogenesis, excitatory–inhibitory imbalance, cellular stress responses, metabolic impairment and immune activation are convergent themes implicated in hippocampal dysfunction in MDD, offering mechanistic insight and a resource for future translational work.