Abstract
Individual susceptibility determines the magnitude of stress effects on cognitive function. The hippocampus, a brain region of memory consolidation, is vulnerable to stressful environments, and the impact of stress on hippocampus may determine individual variability in cognitive performance. Therefore, the purpose of this study was to define the relationship between the divergence in spatial memory performance under chronically unpredictable stress and an associated transcriptomic alternation in hippocampus, the brain region of spatial memory consolidation. Multiple strains of BXD (B6 × D2) recombinant inbred mice went through a 4-week chronic variable stress (CVS) paradigm, and the Morris water maze (MWM) test was conducted during the last week of CVS to assess hippocampal-dependent spatial memory performance and grouped animals into low and high performing groups based on the cognitive performance. Using hippocampal whole transcriptome RNA-sequencing data, differential expression, PANTHER analysis, WGCNA, Ingenuity's upstream regulator analysis in the Ingenuity Pathway Analysis® and phenotype association analysis were conducted. Our data identified multiple genes and pathways that were significantly associated with chronic stress-associated cognitive modification and the divergence in hippocampal dependent memory performance under chronic stress. Biological pathways associated with memory performance following chronic stress included metabolism, neurotransmitter and receptor regulation, immune response and cellular process. The Ingenuity's upstream regulator analysis identified 247 upstream transcriptional regulators from 16 different molecule types. Transcripts predictive of cognitive performance under high stress included genes that are associated with a high occurrence of Alzheimer's and cognitive impairments (e.g., Ncl, Eno1, Scn9a, Slc19a3, Ncstn, Fos, Eif4h, Copa, etc.). Our results show that the variable effects of chronic stress on the hippocampal transcriptome are related to the ability to complete the MWM task and that the modulations of specific pathways are indicative of hippocampal dependent memory performance. Thus, the divergence in spatial memory performance following chronic stress is related to the unique pattern of gene expression within the hippocampus.
Highlights
The incidence rate of neurological diseases and disorders, especially related to cognition and memory performance, has dramatically increased in recent years (UN, 2015)
The average time to locate the platform across the 5 days was determined (Figure 2A; Morris water maze (MWM) performance: mean = 24.67, median = 23.82, SD = 7.62, range: 26.55, CV = 30.90), and utilized to group animals based upon the distribution of their performance
There was a significant group difference in the average of total distance moved during the 5 MWM days (Figure 2D), but no significant difference in the distance moved during the probe trial was detected (Figure 2E)
Summary
The incidence rate of neurological diseases and disorders, especially related to cognition and memory performance, has dramatically increased in recent years (UN, 2015). Chronic stress is generally known to induce adverse effects on brain and brain performance, the destructive effects of stress on hippocampal structures and memory function can vary widely across individuals. This variance in stress effects on individual performance is observed in rodents, where a recent publication (Shea et al, 2015) showed a wide variance in spatial learning performance in mice under prolonged stressful conditions
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