45. SPATIAL TRANSCRIPTOMICS REVEALS BRAIN-WIDE CHANGES IN GENE EXPRESSION ASSOCIATED WITH PROPHYLACTIC EFFECTS OF NORTRIPTYLINE IN A MOUSE MODEL OF CHRONIC STRESS EXPOSURE

• Published in: European neuropsychopharmacology 2024-10, Vol.87, p.73-74
• Main Authors: Yang, Yuanhao, Tannenberg, Rudolph, Hafey, Katelyn, Zhou, Mei, Groves, Natalie, Jhaveri, Dhanisha, Gratten, Jacob
• Format: Article
• Language: English
• ISSN: 0924-977X
• DOI: 10.1016/j.euroneuro.2024.08.159

Anxiety and depression are common psychiatric disorders that affect over 10% of the population worldwide. Large-scale genetic studies have identified > 100 genomic regions associated with risk of anxiety and depression. Environmental risk factors, such as chronic and uncontrollable stress, also play an important role in pathogenesis. However, our understanding of the cellular and molecular changes underlying stress-induced anxiety and antidepressant response remains unclear. We used the 10X Genomics Visium platform to generate spatial transcriptomics data in brain samples from a mouse model of stress-induced anxiety (n=38,395 spatial gene expression measurements), including mice treated with (i) corticosterone (CORT; n=5), (ii) both CORT and the anti-depressant nortriptyline (CORT+NORT; n=6), and (iii) placebo (VEH; n=5). We applied unsupervised graph-based clustering to the spatial gene expression data, identifying 26 clusters that faithfully recapitulated known morphology. We performed spatially-resolved differential expression analyses and pathway analyses, focusing on clusters from the hippocampal, thalamic and cortical regions, to identify genes disrupted by corticosterone (CORT vs VEH) and genes altered by nortriptyline in the presence of corticosterone (CORT+NORT vs CORT). Corticosterone treatment was associated with a mean difference in anxiety-like behaviour (latency to feed test) that was rescued by nortriptyline. Spatial differential expression testing revealed profound disruption of the transcriptome in the hippocampus, thalamus and cortex, involving coordinated expression changes at hundreds of genes (FDR < 0.05), many of which were robust to adjustment for spatial autocorrelation and non-independence of spatial gene expression measures within individual sections. Notably, there was strong evidence for global reversal of CORT-induced expression changes by NORT. Four particularly interesting genes that were disrupted by CORT and rescued by NORT were NEGR1, SLC30A9, CKB and SELENOP, all of which showed independent evidence for significant associations with major depression using human data. Our results provide novel insights into the spatially resolved gene expression changes underpinning stress-induced anxiety and anti-depressant response. Nothing to disclose.