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. 2009 Aug 24:3:14.
doi: 10.3389/neuro.08.014.2009. eCollection 2009.

Early-life programming of later-life brain and behavior: a critical role for the immune system

Staci D Bilbo  1 , Jaclyn M Schwarz
Affiliations

Early-life programming of later-life brain and behavior: a critical role for the immune system

Staci D Bilbo et al. Front Behav Neurosci. .

Abstract

The immune system is well characterized for its critical role in host defense. Far beyond this limited role however, there is mounting evidence for the vital role the immune system plays within the brain, in both normal, "homeostatic" processes (e.g., sleep, metabolism, memory), as well as in pathology, when the dysregulation of immune molecules may occur. This recognition is especially critical in the area of brain development. Microglia and astrocytes, the primary immunocompetent cells of the CNS, are involved in every major aspect of brain development and function, including synaptogenesis, apoptosis, and angiogenesis. Cytokines such as tumor necrosis factor (TNF)alpha, interleukin [IL]-1beta, and IL-6 are produced by glia within the CNS, and are implicated in synaptic formation and scaling, long-term potentiation, and neurogenesis. Importantly, cytokines are involved in both injury and repair, and the conditions underlying these distinct outcomes are under intense investigation and debate. Evidence from both animal and human studies implicates the immune system in a number of disorders with known or suspected developmental origins, including schizophrenia, anxiety/depression, and cognitive dysfunction. We review the evidence that infection during the perinatal period of life acts as a vulnerability factor for later-life alterations in cytokine production, and marked changes in cognitive and affective behaviors throughout the remainder of the lifespan. We also discuss the hypothesis that long-term changes in brain glial cell function underlie this vulnerability.

Keywords: anxiety; cytokines; depression; infection; interleukin-1; memory; microglia; schizophrenia.

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Figures

Figure 1
Figure 1
Early-life infection alters memory, cytokine expression, and microglial activation after a subsequent immune challenge in adulthood. (A) Mean (+SEM) percent freezing during the context pre-exposure task. Neonatal E. coli infection impairs memory formation in adulthood only in the presence of a subsequent immune challenge, LPS (white bars; *p < 0.05 from all other groups) (adapted from Bilbo et al., 2005a). (B) Mean (+SEM) relative gene expression of IL-1β and BDNF in the hippocampus during the context pre-exposure task. Neonatal E. coli infection induces a more than three-fold increase in the transcription of IL-1β only when exposed in adulthood to LPS (white bars). Animals infected neonatally with E. coli also show the greatest decrease in hippocampal BDNF levels 4 h after context pre-exposure and subsequent LPS (*p < 0.05 compared to Vehicle treated animals from same neonatal treatment group; #p < 0.05 compared to Control) (adapted from Bilbo et al., 2008a). (C) Mean (+4 SEM) relative gene expression of MHC II in the hippocampus, a marker of microglial activation. MHC II activity in response to a vehicle injection (black bars) is low in both groups. Neonatal E. coli infection combined with adult LPS (white bars) significantly increases microglial activation above all other treatment groups (*p < 0.05). These data are consistent with the idea of glial priming, illustrated by the cartoon pictorials, in that neonatal infection can permanently activate or “prime” microglia leading to an exaggerated response to LPS.
Figure 2
Figure 2
Early brain development is a sensitive period for long-term changes in glial cell function. Bone marrow-derived mononuclear cells infiltrate the brain in rodents beginning around embryonic day (E) 14, where they eventually differentiate into fully mature, ramified microglia by ∼P14. Microglia are critical for early brain development, and exist primarily in an amoeboid/phagocytic state during this time, and can respond vigorously to infection or injury (e.g., cytokine production). In adulthood as well, quiescent microglial can rapidly transition into an activated state in response to infection or injury. We hypothesize that a subset of glia are permanently maintained in an activated or primed state (represented by the dashed line) into adulthood as a consequence of neonatal infection. Thus, when animals are exposed to a subsequent immune challenge in adulthood, primed microglia produce exaggerated levels of cytokines, which in turn impair memory. Early-life priming of microglial function likely has life-long consequences for brain function, homeostasis, and ultimately behavior.
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