Identification of traumatic brain injury induced molecular signatures using spatial transcriptomics
Bibliographic record
Abstract
BACKGROUND: Traumatic brain injury (TBI) results in multifaceted neuropathology including neuroinflammation, neuronal loss, axonal damage and blood brain barrier damage, which can lead to cognitive impairment and dementia including Alzheimer's disease (AD) and related dementias (ADRDs). Detailed analysis of the molecular and cellular changes that occur in injured brain is crucial to understand TBI's contributions to dementia and AD. The Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) is a non-surgical model of impact-acceleration injury that mimics the biomechanics and pathophysiology of human TBI. METHODS: Adult male mice received a mild CHIMERA injury (2.1J) and acute neurological deficits were assessed as compared to sham group. At 7 days post-TBI, cardiac blood was collected for biomarker analysis and brain was harvested for 10x genomics Visium spatial transcriptomic and multiplexed fluorescence in situ hybridization (mFISH) analysis. RESULTS: Injured mice showed delayed righting reflex recovery and poor performance on neurological tests. Increased plasma glial fibrillary acidic protein (GFAP) and neurofilament light levels (NfL) were found in TBI compared to sham mice. We identified widespread (6614 DEGs: 82% downregulated, 18% upregulated) as well as regional cell type specific gene dysregulation in several clusters. We cross-referenced our dataset with genes identified in human genome wide association studies in AD and TBI and found conserved genes in all three datasets (Ace, AdamTS4, AdamTS1, Trem2, ApoE, Cacna1a, RbFox1, Clu, Apoc1, Mapt). In the optic tract cluster, we identified that the astrocytic marker Gfap, microglial marker Aif1 and several disease-associated microglia (DAMs) genes including Apoe, Ctsd, Trem2 were upregulated. GFAP immunolabelling confirmed astrogliosis in optic tract and hippocampus. In the neocortical cluster, we found downregulation of Itm2c, a negative regulator of amyloid-beta peptide production, and Scg5, a chaperone protein that prevent aggregation of secreted proteins associated with neurodegeneration, which may contribute to TBI-associated susceptibility to AD. mFISH labelling validated downregulation of these genes in cortex. CONCLUSIONS: Our data-rich spatial transcriptomics approach identified molecular and cellular substrates crucial to TBI pathology and its comorbidities including AD and ADRD. Together, this work will provide spatial molecular maps of diffuse brain injury and novel insights into TBI's contributions to dementia.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".