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. 2023 Aug 9;4(1):336-345.
doi: 10.1016/j.bpsgos.2023.08.001. eCollection 2024 Jan.

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors

Alice Hill  1 , Huzefa Khalil  1 , Klaudia Laborc  1 , Savannah Kounelis-Wuillaume  1 , Swapnil Gavade  1 , Colin Johnston  1 , Benjamin H Singer  1   2 , Joanna L Spencer-Segal  1   3
Affiliations

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors

Alice Hill et al. Biol Psychiatry Glob Open Sci. .

Abstract

Background: Millions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors.

Methods: Male and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms.

Results: Long-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes.

Conclusions: Corticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.

Keywords: Anxiety; Glucocorticoids; Illness; PTSD; Sepsis; Stress.

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Figures

Figure 1
Figure 1
Sickness and recovery after CLP with and without corticosteroid treatment. (A) Experimental timeline. (B) (Left panel) Baseline locomotion. (Right panel) One day after surgery, CLP mice were less active than sham mice (n = 40 mice/group). (C) Corticosterone treatment prevented weight loss in CLP animals in the week immediately after surgery; CLP animals that were treated with vehicle lost more weight than the 4 other groups (VEH+sham: n = 20; CORT+sham: n = 17; VEH+CLP: n = 12; CORT+CLP: n = 15). On day 21, 3 weeks after CLP, there was no significant difference in weight change from baseline between groups (sham: n = 20, CLP: n = 18). Error bars show standard error of the mean. ∗p < .05 relative to all other groups based on post hoc tests, ∗∗∗∗p < .0001. CLP, cecal ligation and puncture; CORT, corticosterone; EZM, elevated zero maze; FST, forced swim test; OF, open field; OR, object recognition; VEH, vehicle.
Figure 2
Figure 2
Affective behavior after CLP with and without corticosterone treatment. In the open field test (A–C), CLP survivors explored the entire arena less (A), spent similar amounts of time in the center (B), and exhibited a trend toward fewer entries into the center (C) (p = .052); corticosterone treatment did not prevent these anxiety-like behaviors. Heat maps show the activity of representative typical and anxiety-like behavior in the open field. In the elevated zero maze test (D–G), CLP survivors exhibited anxiety-like behavior, including decreased total exploration (D), time spent in the open area (E), and frequency of head peaks into the open area (G) without affecting the frequency in the open area (F). Again, corticosterone treatment did not prevent the effect of CLP in the elevated zero maze test (sham: n = 40, CLP: n = 32 for open field and elevated zero maze tests). In the forced swim test (H), CLP had no effect on swimming distance or time spent immobile. There was an independent effect of corticosterone treatment to decrease the time spent immobile (I) (sham: n = 20, CLP: n = 14 for forced swim test). Error bars show standard error of the mean. Statistical analysis by three-way analysis of variance for (A–I). ∗p < .05, ∗∗p < .01, ∗∗∗p < .001. CLP, cecal ligation and puncture.
Figure 3
Figure 3
Object memory after CLP with and without corticosterone treatment. In an object recognition test in which both training and testing sessions occurred after recovery, CLP decreased total object exploration during training (A) but not testing (B). (C) Novel object fraction represents the proportion of total exploration time spent with the novel object. All groups demonstrated object memory based on one-sample t tests. There was a significant effect of corticosterone to decrease the novel object fraction toward the chance value, suggesting that corticosterone treatment impaired later object memory formation independent of CLP (sham: n = 40, CLP: n = 32). Statistical analysis by three-way analysis of variance for (A) and (B). Statistical analysis by both one-sample t tests and three-way analyses of variance for (C). ∗p < .05, ∗∗∗p < .001. Error bars show standard error of the mean. CLP, cecal ligation and puncture.
Figure 4
Figure 4
Hypothalamic-pituitary-adrenal axis activity. Three weeks after surgery, CLP survivor mice demonstrated elevated baseline ACTH (A) but no change in baseline corticosterone (B) (sham: n = 20, CLP: n = 18). CLP did not affect stress-induced ACTH (C) or corticosterone (D). A history of corticosterone treatment had no effect on basal or stress-induced ACTH or corticosterone. Error bars show standard error of the mean. Statistical analysis by three-way analysis of variance for (A–D). ∗∗∗p < .001. ACTH, adrenocorticotropic hormone; CLP, cecal ligation and puncture.
Figure 5
Figure 5
Splenic cell counts. CLP survivor mice showed evidence of ongoing systemic inflammation, with an increased proportion of myeloid cells (A), neutrophils (B), and monocytes (C) and a decreased proportion of B and T cells (D–E). Corticosterone also decreased the T cell population independently of CLP (D) but had no effect on the other cell populations. n = 10 for sham+vehicle and sham+corticosterone, 9 for CLP+vehicle and CLP+corticosterone. Error bars show standard error of the mean. ∗p < .05, ∗∗∗∗p < .0001. CLP, cecal ligation and puncture.
Figure 6
Figure 6
(A) Poisson distance heatmap for all samples showing clear separation between samples from the dorsal and ventral hippocampus and then between samples from male and female mice, demonstrating that these factors explain most of the variation between samples. (B) Heatmap of the log-fold change top 500 genes (by p value) in the CLP vs. sham and CORT vs. VEH comparisons ordered based on log-fold change. (C) Venn diagram showing the number of significant genes (at a false discovery rate–corrected p value of .05) in CORT vs. VEH and CLP vs. sham comparisons. We saw 2082 genes that were significant in the former and 109 genes that were significant in the latter, and only 6 genes were significantly changed in both comparisons. n = 7 sham-CORT-male, n = 8 sham-CORT-female, n = 8 sham-VEH-male, n = 7 sham-VEH-female, n = 8 CLP-CORT-male, n = 6 CLP-CORT-female, n = 5 CLP-VEH-male, n = 6 CLP-VEH-female. CLP, cecal ligation and puncture; CORT, corticosterone; VEH, vehicle.
Figure 7
Figure 7
Top 30 pathways from a gene set enrichment analysis of the CLP vs. sham (A) and CORT vs. VEH (B) comparisons. The analysis was conducted using the Gene Ontology pathways, specifically the pathways related to biological processes. The pathways are connected if there is a >30% overlap between them. CLP caused upregulation to pathways regulating leukocyte function and inflammation, while the primary pathways altered by corticosterone included many nonoverlapping pathways in the areas of regulation of gene expression, hormone and cellular signaling, and development and differentiation. n = 7 sham-CORT-male, n = 8 sham-CORT-female, n = 8 sham-VEH-male, n = 7 sham-VEH-female, n = 8 CLP-CORT-male, n = 6 CLP-CORT-female, n = 5 CLP-VEH-male, n = 6 CLP-VEH-female. CLP, cecal ligation and puncture; CORT, corticosterone; VEH, vehicle.
Figure 8
Figure 8
Correlation of activity-dependent gene expression and behavior. Fold change of the activity-dependent genes in the tan module in the corticosterone vs. saline comparison, shown separately for the sham and CLP groups, shows downregulation of gene expression by corticosterone. CLP, cecal ligation and puncture; CORT, corticosterone.
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