Abstract

Effect of Glucocorticoid Treatment During Acute Infectious Illnesson Hippocampal Function in Survivors

Hill A, Khalil H, Laborc K, Kounelis-Wuillaume S, Johnston C, Agranoff I, Gavade S, Singer B, Akil H, Spencer-Segal JL
61st Annual Meeting of the American College of Neuropsychopharmacology. 2022.

Abstract

Background: Neuropsychiatric symptoms afflict half of survivors of critical illnesses leading to substantial public health burden. Glucocorticoids are commonly administered to acutely ill patients for their cardiovascular and anti-inflammatory properties, but they also influence brain outcomes. Intriguingly, observational and randomized clinical trials show that glucocorticoid treatment during critical illness decreases the risk of post-traumatic stress disorder (PTSD) in survivors, but the mechanisms are unknown. We hypothesized that glucocorticoid treatment during illness might influence hippocampal-dependent emotional and/or cognitive processes in survivors.

Methods: We used cecal ligation and puncture (CLP) to induce systemic infection in male and female mice (N = 80 divided equally among groups) and treated them with corticosterone (16 mg/kg) or vehicle during the acute illness (Days 1-5). Illness severity was measured using locomotion and daily weights. Beginning on Day 14, we studied affective behavior and neuroendocrine function. The Open Field and Elevated Plus Maze were used to measure negative affect, while the Object Recognition test was used to measure memory. Basal and stress-induced (forced swim) ACTH and corticosterone were measured from plasma using an ELISA, and systemic inflammation was measured using splenic cell counts by flow cytometry. Dorsal and ventral hippocampi were dissected from half the mice and RNA was isolated and prepared for paired-end 50 bp RNA Sequencing, which was performed on an Illumina NovaSeq S4.

Results: Corticosterone prevented CLP-induced weight loss without significantly affecting sickness-induced locomotor behavior or overall survival. After a 14-day recovery, male and female CLP survivor mice showed persistent negative affect based on decreased exploration of open areas in the Open Field and Elevated Plus Maze, and this was not rescued by corticosterone treatment. On the other hand, corticosterone treatment during illness impaired survivors’ performance on the Object Recognition test. CLP survivor mice showed evidence of enhanced central hypothalamic-pituitary-adrenal (HPA) axis activity based on elevated basal ACTH levels, but corticosterone treatment during illness had no effect on HPA axis function in survivors. There was also evidence of persistent systemic inflammation in CLP survivors based on splenic cell counts that was not rescued by corticosterone treatment.

RNA sequencing showed distinct neural signatures of CLP and corticosterone treatment. 103 genes were differentially expressed in CLP survivors and 2076 genes were differentially expressed after corticosterone treatment, with only 6 overlapping genes. CLP survivors showed persistent upregulation of inflammation- and immunity-related genes, which were not altered by corticosterone treatment. Correlation of behavior in the Elevated Plus Maze with gene expression revealed a set of 126 genes in the ventral hippocampus that related to affective behavior after CLP, most of them involved in neuroendocrine signaling rather than inflammatory or immune processes.

Conclusions: In summary, murine survivors of CLP-induced acute infectious illness showed persistent negative affect and heightened central HPA axis activation. While persistent systemic and neuro-inflammation was seen in CLP survivors, correlation of gene expression with behavior related altered neuroendocrine signaling in the ventral hippocampus, rather than neuroinflammation, to affect in CLP survivors. Corticosterone treatment during illness did not rescue negative affect in survivors, but it impaired object memory and altered the expression of 10% of the detectable transcripts in the dorsal and ventral hippocampus. These findings provide the first separation of mechanisms related to affective and cognitive impairments after acute illness. The data suggest that neuroendocrine signaling in the ventral hippocampus is important for emotional outcomes while highlighting a role for glucocorticoids in cognitive outcomes. Future work will pursue the resulting hypothesis that glucocorticoids may alter the risk for PTSD by altering hippocampal-dependent memory processes.