Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline

Abstract

There is significant individual variability in cognitive decline during aging, suggesting the existence of "vulnerability factors" for eventual deficits. Neuroinflammation may be one such factor; increased glial reactivity is a common outcome of aging, which in turn is associated with numerous neurodegenerative conditions. Early-life infection leads to cognitive impairment in conjunction with an inflammatory challenge in young adulthood, which led us to explore whether it might also accelerate the cognitive decline associated with aging. Rats were treated on postnatal day 4 with PBS or Escherichia coli, and then tested for learning and memory at 2 or 16months of age, using two fear-conditioning tasks (context pre-exposure and ambiguous cue), and a spatial water maze task. Neonatally-infected rats exhibited memory impairments in both the ambiguous cue fear-conditioning task and in the water maze, but only at 16months. There were no differences in anxiety between groups. Neonatally-infected rats also exhibited greater aging-induced increases in glial markers (CD11b and MHCII on microglia, and GFAP on astrocytes), as well as selective changes in NMDA receptor subunit expression within the hippocampus, but not in amygdala or parietal cortex compared to controls. Taken together, these data suggest that early-life infection leads to less successful cognitive aging, which may be linked to changes in glial reactivity.

Figure 1. Percent freezing to the context in the pre-exposure task does not differ among groups

Rats were treated on postnatal day (P) 4 with PBS or E. coli, and tested for memory at 2 month or 16 month of age using a task which requires the animal to make a simple association between a shock and exploration of a novel environment the previous day. There were no significant differences as a consequence of either age or neonatal treatment.

Figure 2. Older rats infected as neonates exhibit a cognitive impairment in the ambiguous cue task

Rats were treated on P4 with PBS or E. coli, and tested for memory at 2 month or 16 month of age using a task that requires the animal to distinguish between multiple cues that predict a shock with varying fidelity. Figures represent percent freezing to each cue minus baseline (“no cue”) freezing at 48 hr (A) or 1 wk (B) after conditioning. *freezing to the light is significantly different overall from freezing to the tone; **freezing is overall higher in 16 month compared to 2 month old rats; #significantly different from PBS/Tone group; p<0.05 for all.

Figure 3. Water maze performance depends on neonatal treatment and age

Rats were treated on P4 with PBS or E. coli, and tested for spatial learning & memory at 2 month or 16 month of age using a hidden platform task. Rats infected as neonates acquired the task faster than PBS controls at 2 months (A) but not at 16 months (B) of age. (C) Performance during the probe trials: Difference score = time in the platform quadrant minus time in the next best quadrant for each rat, indicative of selective searching in the target platform; *significantly different from PBS at the same time point, p<0.05.

Figure 4. Older rats exhibit more anxiety than young rats

Rats were treated on P4 with PBS or E. coli, and tested for anxiety at 2 months (A) or 16 months (B) of age. Time spent in the open vs. closed arms of the elevated plus maze did not differ between neonatal treatment groups at either age, but 2 month old rats spent significantly more time in the open arms than older rats, **p<0.05.

Figure 5. Glial markers and NMDA receptor subunit composition are altered with age

Rats treated on P4 with PBS or E. coli were sacrificed at 2 or 16 month of age, following the completion of behavioral testing. All statistics were performed on raw data, but data are presented here as relative changes in gene expression in the 16 month olds compared to 2 month olds in order to better illustrate age-associated changes. #significantly different overall from 2 month olds, *significantly different overall from PBS, **significantly different from PBS within the dentate gyrus (DG), p<0.05 for all. CD11b=complement 3 receptor, a marker for microglia; MHC II=major histocompatibility complex, a marker for microglia; GFAP=glial fibrillary acidic protein, a marker for astrocytes; AMY=Amygdala; PAR=parietal cortex.