New Investigator AwardEnduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain
Introduction
Microglia are the primary immunocompetent cells of the brain, with demonstrated roles in both protection and pathology. For instance, they appear to be neuroprotective following stroke, by producing trophic factors that aid in cellular repair (Lalancette-Hebert et al., 2007). In contrast, chronic or exaggerated microglial activation is associated with multiple neuroinflammatory diseases, including Parkinson’s, Alzheimer’s, and Huntington’s disease (Perry, 2004). Activated microglia produce many factors, including superoxide, nitric oxide, and cytokines, that may lead to neuronal damage or interfere with neuronal function directly (Block et al., 2007). Microglial activation is also associated with multiple neurodevelopmental disorders with known or suspected immune etiologies, including autism, schizophrenia, and cerebral palsy, although the direction of causality in the majority of these disorders is unknown (Bilbo and Schwarz, in press, Meyer et al., 2005, Vargas et al., 2005).
We have reported that systemic infection with Escherichia coli on postnatal day (P) 4 in rats is associated with marked hippocampal-dependent memory impairments in adulthood. However, these impairments are only observed if a second immune challenge (bacterial lipopolysaccharide [LPS]) is administered in close proximity to learning in adulthood (Bilbo et al., 2005a, Bilbo et al., 2005b). The impairment is linked to exaggerated pro-inflammatory cytokine production to the LPS challenge, and decreased learning-induced brain-derived-neurotrophic factor (BDNF) expression within the hippocampus, a growth factor critical for memory consolidation (Bilbo et al., 2008, Bilbo et al., 2007). Importantly, this low dose of LPS does not impair memory in control rats. Thus, infection during the neonatal period appears to act as a “vulnerability” factor, by amplifying the adult rat’s central cytokine response to the LPS challenge, which then impairs cognition.
We have hypothesized that the basis for this vulnerability may be long-term changes in glial cell function. Microglia are the primary cytokine producers within the brain, and are an excellent candidate for long-term changes, because they are long-lived and can become and remain activated chronically (Town et al., 2005). There is increasing support for the concept of “glial priming”, in which cells can become sensitized by an insult, challenge, or injury, such that subsequent responses to a challenge are exaggerated (Perry et al., 2003). Notably, the first week of life in rats is a time of extensive brain growth, when microglial proliferation, migration, and density peak (Bayer et al., 1993, Wu et al., 1992). Thus, the early postnatal stage may be particularly vulnerable to insult, with subsequent long-term changes in microglial cell function.
In support of this hypothesis, we have reported increases in glial cell “activation” markers in our infection model (e.g., CD11b [complement 3 receptor], and major histocompatibility complex [MHC] II), both acutely in response to the E. coli, as well as in adulthood following the LPS challenge (Bilbo et al., 2005a, Bilbo et al., 2007, Bilbo and Schwarz, in press). However, the functional consequences of observed “activation” is unknown. For instance, an increase in overall activation markers could indicate an increase in the reactivity of the same number of cells, or conversely an increase in the number of cells, without a change in function. Distinguishing between these two possibilities is critical for establishing causality, as well as eventual treatment options. Moreover, the neuronal responses to both the early E. coli and the adult LPS are completely unknown. Neurons constitutively inhibit microglial activity via interactions with factors such as the CD200 receptor expressed exclusively on microglia (Barclay et al., 2002, Lyons et al., 2007). Thus, any decrease in neurogenesis or survival by early-life infection could have enduring effects on glial cell reactivity via reduced inhibitory tone. Finally, an emerging literature implicates inflammation as an important factor in regulating neurogenesis within the adult brain (Whitney et al., 2009), but the influence of early-life inflammation on later-life responses is virtually unknown. Thus, the goal of these experiments was to (1) assess glial and neural cell proliferation and survival following infection with E. coli on day 4, and (2) assess the glial and neuronal cell responses to the subsequent LPS challenge in adulthood.
Section snippets
Animals
Adult male and female Sprague–Dawley rats (70 days) were obtained from Harlan (Indianapolis, IN) and housed in same sex pairs in polypropylene cages with food and water freely available. The colony was maintained at 22 °C on a 12:12-h light:dark cycle (lights on at 0600 MST). Following acclimation to experimental conditions, males and females were paired into breeders. Sentinel animals were housed in the colony room and screened periodically for the presence of common rodent diseases; all screens
Experiment 1
The effects of neonatal E. coli infection on precursor cell proliferation and neuro/gliogenesis.
Discussion
We have hypothesized that the basis for early-life infection-induced vulnerability to altered cytokine expression and cognitive deficits in adulthood may be due to long-term changes in glial cell function and/or influences on subsequent neural development. E. coli infection on P4 markedly increased microglial proliferation in the CA regions of the hippocampus and PAR of newborn pups, compared to a PBS injection (Fig. 3, Fig. 4). The total number of microglia, and specifically microglia with an
Acknowledgments
The authors thank Andrea Eads, Jessica Bolton, and Brandon Marsh for technical assistance. Supported in part by a NARSAD Young Investigator Award to STB, and R01MH083698 to SDB.
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