Chronic stress beginning in adolescence decreases spatial memory following an acute inflammatory challenge in adulthood

Abstract

Prolonged stress beginning in adolescence can contribute to the dysregulation of the neuroendocrine system in adulthood. As the neuroendocrine and neuroimmune systems participate in bi-directional regulatory control, adolescent stress can prime the neuroimmune system to future inflammatory insults. Previous work from our group demonstrates that stress exaggerates the hippocampal response to inflammation, which can lead to deficits in learning and memory. In the current study, we sought to interrogate the interaction between an acute peripheral challenge of lipopolysaccharide (LPS) in male and female Wistar rats with a history of stress beginning in adolescence (CAS). Males from the CAS group were more vulnerable to the peripheral effects of LPS compared to non-stressed males including porphyrin staining and ruffled fur. In contrast, LPS generated similar peripheral effects in females regardless of adolescent stress history. Learning and memory were differentially impacted by LPS as a function of stress history and effects manifested differently when stratified by sex. Males with a history of adolescent stress exhibited deficits in initial learning. Females from the CAS group performed similar to controls during acquisition but exhibited a slight impairment during reversal learning. Males and females with a history of stress displayed memory impairment during the probe assessments as compared to their same-sex control group. We conclude that while stress beginning in adolescence enhanced the vulnerability of learning and memory to an inflammatory challenge, the phenotype of this effect manifested differently in males and females. These data demonstrate a sustained impact of adolescent stress on the neuroimmune system which is sufficient to influence cognitive performance in both sexes.

Keywords: Cognition; Inflammation; Sex; Stress.

Figure 1.

(A) Schematic of the experimental timeline. Adolescent male and female Wistar rats underwent a chronic mixed modality stress paradigm. As adults, rats were given an acute LPS challenge. Rats were assessed for anxiety-like behavior in the Open Field and trained on the Barnes Maze task. (B) During the defeat paradigm, female rats experienced a longer latency to pin (B) and fewer pins (C) compared to males. (D) For both males and females, regardless of stress history, LPS treatment caused a reduction in weight. In males, weight did not return to baseline until twelve days post injection. For females, weight returned to baseline after seven days post injection. Overall, males weighed more than females. Males with a history of chronic stress were more susceptible to the physical effects of LPS treatment compared to non-stress males. They showed higher levels of (E) ruffled fur and (F) porphyrin staining. Females with a history of stress showed similar, but attenuated, deficits compared to non-stress controls. There were no effects of stress history or sex on (G) diarrhea. Symbols represent mean ± SEM. *, main effect of sex (p<0.05); #, main of effect of stress (p<0.05); †, main effect of day (p<0.05). Panel A was created using the Biorender illustration tool available at Biorender.com.

Figure 2.

During acquisition learning, males with a history of stress had an increased latency to locate the goal box compared to non-stress males (A). There were no effects of stress history on (B) errors or (C) velocity. Acquisition learning in females was not altered by stress history. During reversal learning, females with a history of stress (D) showed a slight impairment in the latency to locate the goal box compared to non-stress females. (E) Non-stress females showed more errors on days one and three compared to CAS females. (F) CAS females appeared to move slightly slower than non-stress females. Performance in males was not altered by stress history during reversal learning (D). Females with a history of stress had longer latencies to locate the goal box position during probe 1 (G), while stressed males took longer during probe 2(K). I) During probe 1, females with a history of stress were less likely to revisit the goal box compared to non-stress animals. There were no differences in (H, L) error rates or (J, N) velocity in either probe. Symbols represent mean ± SEM. #, main effect of stress (p<0.05); †, interaction between stress and training day (p<0.05).