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Updated: May 28, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglia and memory: modulation by early-life infection
Lauren L Williamson1, Paige W Sholar, Rishi S Mistry
1Department of Psychology and Neuroscience, Duke University, Durham, North Carolina 27708, USA.
Abstract:
The proinflammatory cytokine interleukin-1β (IL-1β) is critical for normal hippocampus (HP)-dependent cognition, whereas high levels can disrupt memory and are implicated in neurodegeneration. However, the cellular source of IL-1β during learning has not been shown, and little is known about the risk factors leading to cytokine dysregulation within the HP. We have reported that neonatal bacterial infection in rats leads to marked HP-dependent memory deficits in adulthood. However, deficits are only observed if unmasked by a subsequent immune challenge [lipopolysaccharide (LPS)] around the time of learning. These data implicate a long-term change within the immune system that, upon activation with the "second hit," LPS, acutely impacts the neural processes underlying memory. Indeed, inhibiting brain IL-1β before the LPS challenge prevents memory impairment in neonatally infected (NI) rats. We aimed to determine the cellular source of IL-1β during normal learning and thereby lend insight into the mechanism by which this cytokine is enduringly altered by early-life infection. We show for the first time that CD11b(+) enriched cells are the source of IL-1β during normal HP-dependent learning. CD11b(+) cells from NI rats are functionally sensitized within the adult HP and produce exaggerated IL-1β ex vivo compared with controls. However, an exaggerated IL-1β response in vivo requires LPS before learning. Moreover, preventing microglial activation during learning prevents memory impairment in NI rats, even following an LPS challenge. Thus, early-life events can significantly modulate normal learning-dependent cytokine activity within the HP, via a specific, enduring impact on brain microglial function.
Insights
Neonatal infection sensitizes brain microglia, leading to increased interleukin-1β (IL-1β) during learning. This early-life event impacts adult memory function, highlighting microglial role in cognitive deficits.
Area of Science:
- Neuroscience
- Immunology
- Cognitive Science
Background:
- Interleukin-1β (IL-1β), a proinflammatory cytokine, is crucial for hippocampus-dependent memory but elevated levels impair cognition and are linked to neurodegeneration.
- The cellular origin of IL-1β during learning and factors contributing to its dysregulation in the hippocampus (HP) remain unclear.
- Neonatal bacterial infection in rats causes long-term HP-dependent memory deficits, particularly when reactivated by a secondary immune challenge (lipopolysaccharide, LPS) during adulthood.
Purpose of the Study:
- To identify the specific cell type responsible for producing IL-1β during normal hippocampus-dependent learning.
- To investigate how early-life infection influences the cellular source of IL-1β and its contribution to memory impairment.
- To elucidate the mechanism by which early-life events permanently alter cytokine activity in the brain's immune cells.
Main Methods:
- Utilized CD11b(+) cell enrichment to isolate and analyze cytokine production in the hippocampus.
- Assessed ex vivo IL-1β production from CD11b(+) cells in neonatally infected (NI) rats compared to controls.
- Investigated the role of microglial activation during learning in memory performance in NI rats, with and without LPS challenge.
Main Results:
- Demonstrated that CD11b(+) enriched cells are the primary source of IL-1β during normal hippocampus-dependent learning.
- Found that CD11b(+) cells from NI rats exhibit functional sensitization, producing exaggerated IL-1β ex vivo.
- Showed that preventing microglial activation during learning rescues memory deficits in NI rats, even after an LPS challenge.
Conclusions:
- Early-life infections can induce lasting changes in brain microglial function, altering their response during learning.
- Microglia are the key cellular mediators of IL-1β dysregulation in the hippocampus following early-life adversity.
- Modulating microglial activity during learning presents a potential therapeutic target for preventing cognitive deficits associated with early-life insults.
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