Creation of a gene expression portrait of depression and its application for identifying potential treatments

Abstract

Depression is a complex mental health disorder and the goal here was to identify a consistent underlying portrait of expression that ranks all genes from most to least dysregulated and indicates direction of change relative to controls. Using large-scale neural gene expression depression datasets, a combined portrait (for men and women) was created along with one for men and one for women only. The depressed brain was characterized by a “hypo” state, that included downregulation of activity-related genes, including EGR1, FOS, and ARC, and indications of a lower brain temperature and sleep-like state. MAP kinase and BDNF pathways were enriched with overlapping genes. Expression patterns suggested decreased signaling for GABA and for neuropeptides, CRH, SST, and CCK. GWAS depression genes were among depression portrait genes and common genes of interest included SPRY2 and PSEN2. The portraits were used with the drug repurposing approach of signature matching to identify treatments that could reverse depression gene expression patterns. Exercise was identified as the top treatment for depression for the combined and male portraits. Other non-traditional treatments that scored well were: curcumin, creatine, and albiflorin. Fluoxetine scored best among typical antidepressants. The creation of the portraits of depression provides new insights into the complex landscape of depression and a novel platform for evaluating and identifying potential new treatments.

Evaluation of animal model congruence to human depression based on large-scale gene expression patterns of the CNS

“…CRH is associated with anxiety and arousal, has a nonlinear effect on behavior when acting among multiple receptors, and is associated with psychiatric disorders, including depression 20 – 23 . A number of activity related genes, EGR1, FOS, NR4A1, FOSB, and ARC, were downregulated in the model and depression and this is consistent with the idea of the depressed brain being in a 'hypo' state 11 . The upregulation of the cold-induced RNA binding protein (CIRBP) along with decreased expression of multiple heat shock proteins suggests a possible decreased CNS temperature.…”

“…Further, possible models within the BxD recombinant inbred mice lines 48 as well as the collaborative cross mice 49 were not evaluated and it is possible that in future studies, a line with high congruence with depression will be identified. In this study a portrait of human depression was used that incorporated data from 29 human datasets from men and women across multiple brain regions and an advantage is that it provides a single consistent underlying signature of depression across the CNS for comparisons with the models 11 . The results from the separate analysis of the male and female portrait indicate both similarities and differences of matching to animal models.…”

“…For humans with depression, data on large-scale gene expression patterns in the CNS also exist that are derived from postmortem tissue from case MDD and control individuals 5 – 10 . Further, across multiple independent studies in humans, common depression dysregulation patterns have been identified, including dysregulation of MAP kinase signaling pathways 10 , 11 , suggesting that meaningful large-scale gene expression patterns exist with depression. Given large-scale gene expression data in animal models and humans with depression, it should be possible to identify the best matches of animal models to human depression to gain insights into how depression expression patterns can be triggered and what pathways are most commonly dysregulated 11 .…”

“…Further, machine learning that used human data for training and animal models for testing, Uniform Manifold Approximation Plot (UMAP) 14 and Rank Rank Hypergometric Overlap (RRHO) heatmaps 15 were used to evaluate matching of models with human depression. For the main focus of this study, human depression was represented by a single depression portrait that was recently created from 29 human depression datasets from males and females across multiple CNS regions and provides information on consistent patterns of dysregulation in depression across the CNS 11 . To help identify possible sex specific matches for human depression, separate analysis of a male and female portrait of depression with the models was also performed.…”

BDNF Impact on Biological Markers of Depression—Role of Physical Exercise and Training

“…In recent decades, a great deal of knowledge has been accumulated about the neurological mechanisms involved in depression, including the influence of inflammatory factors, the role of monoamines, and the influence of vascular disorders and genetics on the physiopathology of depression, regardless of environmental factors, eventually evolving to malfunction and/or damage to specific neural networks [ 7 , 8 , 9 , 10 , 11 ]. The datasets of gene regulation in depression is created and a combined portrait was created for men and women only [ 12 ]. Impairment of adult neurogenesis, altered nervous processes and synaptic depression, and neuronal atrophy are just some of the neuroplasticity-related processes that are at risk in patients with depression during clinical and experimental studies [ 13 , 14 , 15 ].…”