Figure 4. Learning increases IL-1β protein within hippocampal microglia, which is modulated by neonatal infection.

(A) Neonatally-infected rats and controls were treated in adulthood with saline or lipopolysaccharide (LPS) 24 h prior to either a learning experience (fear conditioning, consisting of 2 min context exploration followed by a footshock), or a control procedure which consisted of footshock only (without context exploration) or context exposure only (no footshock). IL-1β protein was measured in the hippocampus of separate groups of rats from each neonatal condition, 2 h after each of these conditions (shock alone, context alone, or context + shock/fear learning). In rats from both neonatal conditions that received a saline injection as adults, IL-1β protein was only increased after the learning experience (context + shock); *p<0.001, compared to context alone or shock alone. Neonatally-infected rats that received LPS 24 hours prior to behavioral testing exhibited an exaggerated IL-1β response, but only in response to learning (context + shock); **p<0.01 compared to control rats. These data indicate that normal learning induces the synthesis of IL-1β in the hippocampus, but neonatally-infected rats that receive an adult immune challenge have dysregulation of IL-1β at the time of learning. Subsequent experiments revealed that microglia were the sole source of IL-1β in these experiments [307]. (B) In a separate set of rats, fear memory for the context was assessed 72 h after conditioning. Rats from each neonatal condition that received saline 24 h prior to the learning experience show robust freezing behavior (fear) at the 72 h test, indicating that they remember the association between the shock and the context. Control rats that received LPS 24 h prior to conditioning also show robust freezing behavior (fear) at the 72 h test, indicating strong memory. In contrast, neonatally-infected rats that received LPS 24 h prior to conditioning exhibit significantly decreased freezing (fear) in the context (**p<0.05), indicating impaired memory only in this “2-hit” group (neonatal infection + adult immune challenge; see [307]). (C) Our working model is that IL-1β is produced by microglia within the hippocampus at the time of learning and is required for normal memory formation. In the absence of learning (shock alone or context alone), IL-1β is not produced in detectable levels. In neonatally-infected rats, long-term changes in neuroimmune function (microglial priming, see [307]) results in significantly exaggerated levels of IL-1β following a learning experience, which are “unmasked” by the adult LPS challenge. These exaggerated levels of IL-1β interfere with the consolidation of the learning experience and result in memory deficits. The cartoon illustrates microglia in a quiescent phenotype (left-hand tail of the inverted U), in a normal, active phenotype in which IL-1β is produced during normal learning to support memory (center), and in a sensitized/primed morphology in which exaggerated levels of IL-1β are observed in response to learning, but only in neonatally-infected rats that receive LPS as adults (right-hand tail of the inverted U). All data are represented from [307]).