Microglia Modulate Hippocampal Neural Precursor Activity in Response to Exercise and Aging

Abstract

Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX 3 CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blockingantibodyagainsttheCX 3 CL1receptor,CX 3 CR1,butnotcontrolIgG,dramaticallyreducedtheneurosphereformationfrequencyinmice thathadexercised.WhileanincreaseinsolubleCX 3 CL1wasobservedfollowingrunning,reducedlevelsofthischemokinewerefoundintheaged brain.LowerlevelsofCX 3 CL1withadvancingagecorrelatedwiththenaturaldeclineinneuralprecursorcellactivity,astatethatcouldbepartially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX 3 CL1-CX 3 CR1 axis critically contributes toward this process.

Patterns of Change in Cognitive Function Over Six Months in Adults With Chronic Heart Failure

“…Efforts are needed to identify interventions that can effectively prevent and perhaps reverse cognitive decline after HF is diagnosed. Right now, exercise is the most promising approach, as it has been demonstrated to induce an increase in neural precursor cell activity and improve cognition directly [56]. Exercise also could influence the two modifiable predictors identified in this study: BMI and excessive daytime sleepiness.…”

Microglia in steady state

“…Adult microglia regulate postnatal neurogenesis in the hippocampus and SVZ. Whereas aging seems to have a negative effect on microglia, resulting in a decrease in neurogenesis, exercise and environmental enrichment physiologically prime microglia to support adult neurogenesis (104)(105)(106). Exercise enhances hippocampal microglial release of the chemokine CX3CL1, which protects neuronal precursor cells (106).…”

“…Whereas aging seems to have a negative effect on microglia, resulting in a decrease in neurogenesis, exercise and environmental enrichment physiologically prime microglia to support adult neurogenesis (104)(105)(106). Exercise enhances hippocampal microglial release of the chemokine CX3CL1, which protects neuronal precursor cells (106). Additionally, microglia help maintain the hippocampal neurogenic niche in the dentate gyrus via expression of CX3CR1, which mediates the communication and interaction between microglia and neurons in adult mice (103).…”

Neuronal-Glial Mechanisms of Exercise-Evoked Stress Robustness

“…Recent evidence, for example, demonstrates that activated growth/repair microglia are essential during normal neural development (Ekdahl 2012;Paolicelli et al 2011;Schafer et al 2012) and may play a role in adult plasticity changes during learning, memory formation and neurogenesis (Ekdahl et al 2009;Tremblay and Majewska 2011;Williamson et al 2011;Yirmiya and Goshen 2011). In fact, there is some evidence to suggest that physical activity may promote the growth/repair microglia phenotype (Vukovic et al 2012;Ziv et al 2006) and that depletion of microglia can prevent some of the beneficial effects of exercise on learning and memory . In contrast, after exposure to an acute uncontrollable stressor, inflammatory/destructive microglia can release inflammatory mediators that contribute to the negative, cognitive, affective, and neurogenic consequences of stress.…”

“…The CX3CL1-CX3CR1 axis is also involved in physiological processes, including modulation of hippocampal neurogenesis Maggi et al 2011;Rogers et al 2011). Interestingly, the aging brain responds to stressors and pathogens with exaggerated and prolonged microglia activation and inflammatory cytokines responses (Vukovic et al 2012;Wynne et al 2009); and recent evidence suggests that down-regulation of the CX3CL1-CX3CR1 axis plays a major role in this effect Wynne et al 2010). …”