A Lifespan Approach to Neuroinflammatory and Cognitive Disorders: A Critical Role for Glia

Abstract

Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual‘s risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or “re-programming” of this crucial process by external events (e.g, stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life.

The impact of early life immune challenge on behavior and microglia during postnatal development

“…Notably, we observed sex differences in microglial number in the dorsal raphe between SAL-injected male and female mice and treatment effects in male mice in response to LPS in both the PVN and DR. These findings are consistent with the observation that there are increased numbers of microglia in male mice during the first week of postnatal life and increased immune sensitivity in male mice in response to immune challenge during this postnatal window [38,40] . Previous work has shown that in the absence of immune activation, immune genes are upregulated during postnatal development in several brain regions, and sex differences in levels of gene expression have been reported [38] .…”

Early Life Stress Activates Glial Cells in the Hippocampus but Attenuates Cytokine Secretion in Response to an Immune Challenge in Rat Pups

“…For instance, E. coli injected on PN4 rat pups induced immediate microglial activation, which lasted into adult age. The exposure to a second challenge with LPS at an adult age induced a higher activation of microglial cells [16,45]. These results indicated a preactivated stage of the microglia due to the first challenge on PN4.…”

Increased cytokine and chemokine gene expression in the CNS of mice during heat stroke recovery

“…Of particular relevance to the long-term health outcomes associated with recovery from HS is recent evidence that acute increases in brain cytokines can set in motion a prolonged sensitization of glia cells (3,10,13,29). This sensitization, known as glia priming, can lead to a potentiated pro-inflammatory response upon subsequent secondary insults (i.e., peripheral immune challenge, stress, injury, etc.)…”