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ViewAttendees 3

Basic Science

Hippocampal Sex Specific Transcriptomic Changes in Neonatal Mice Following Hypoxia Ischemia and Trkb Agonist Treatment

Friday, September 19, 2025
11:15 AM - 11:30 AM CT
Location: Ann & Robert H. Lurie Children’s Hospital of Chicago, 11th Floor Conference Room 200 E. Superior
Disclosure(s):
Nursena Yabalar, MD: I do not have any relevant financial / non-financial relationships with any proprietary interests.
Background: The hippocampus, crucial for learning and memory, is negatively affected by neonatal hypoxia ischemia (HI) related brain injury. Our previous research identified female biased tyrosine kinase B receptor (TrkB) mediated hippocampal neuroprotection post-HI.

Objectives: In this study, we investigated sex differences in cell-type–specific gene expressions following HI and evaluated the impact of the TrkB agonist 7,8-dihydroxyflavone (DHF) using snRNA-seq.

Design/Methods: Sham or Vannuci's HI surgery was performed on postnatal (P) 9 mice, followed by vehicle or DHF treatment daily for 3 days (n=3–4). Moderately injured hippocampi were selected for snRNA-seq at P12. Sex-specific responses per cell cluster were analyzed in JupyterLab (Python) using Wilcoxon tests; differentially expressed genes (DEGs) were defined as |log₂FC|>0.6 and adj. p< 0.05, and plots were made in R.

Results: We have identified 29 different cell clusters and 9 major cell types from 234,841 nuclei. HI induced greater number of gene up regulation in all major cell clusters in females compared to males. TrkB gene (Ntrk2) was found to be highly expressed in hippocampal interneurons, astrocytes, Cajal-Retzius cells, excitatory neurons, OPCs. Ntrk2 expression was the lowest in microglia (Fig. 1). Ntrk2 expression was found to be statistically significantly higher in females compared to males post-HI in each cluster, with the highest in interneurons and astrocytes. DHF increased the number of genes upregulated in males but decreased in females (Fig. 2) and rescued the genes (up- or down-regulated) in neuronal clusters in males and in glial clusters in females (Fig. 3). Additionally, permutation testing showed significant enrichment of autism spectrum disorder (ASD) risk genes among DEGs in astrocytes, microglia, excitatory neurons, and interneurons across all comparisons (empirical p < 0.05) and highest number of gene changes seen in female astrocyte cluster after administration of the DHF treatment (Fig. 4).

Conclusions: This transcriptomics study revealed sex-specific alterations in hippocampal cell clusters following HI related brain injury and DHF treatment. These findings will help us identify cell-type–specific pathways in which Ntrk2 signaling may play a key role and serve as a potential therapeutic target of DHF. Additionally, the observed sex differences in autism spectrum disorder (ASD) risk gene expression provide a novel direction for future research into sex-specific mechanisms underlying neurodevelopmental disorders.