Microglial activation and adult neurogenesis after brain stroke

The discovery that new neurons are produced in some regions of the adult mammalian brain is a paradigm-shift in neuroscience research.These new-born cells are produced from neuroprogenitors mainly in the subventricular zone at the margin of the lateral ventricle,subgranular zone in the hippocampal dentate gyrus and in the striatum,a component of the basal ganglia,even in humans.In the human hippocampus,neuroblasts are produced even in elderlies.The regulation of adult neurogenesis is a complex phenomenon involving a multitude of molecules,neurotransmitters and soluble factors released by different sources including glial cells.Microglia,the resident macrophages of the central nervous system,are considered to play an important role on the regulation of adult neurogenesis both in physiological and pathological conditions.Following stroke and other acute neural disorders,there is an increase in the numbers of neuroblast production in the neurogenic niches.Microglial activation is believed to display both beneficial and detrimental role on adult neurogenesis after stroke,depending on the activation level and brain location.In this article,we review the scientific evidence addressing the role of microglial activation on adult neurogenesis after ischemia.A comprehensive understanding of the microglial role after stroke and other neural disorders it is an important step for development of future therapies based on manipulation of adult neurogenesis.

Neurogenesis in the hippocampus of adult humans: controversy “fixed” at last

The presence of adult neurogenesis in the mammalian brain has been a theme of intense controversy for a long time since the original report by Altman and Das (1965). The scientific community, for about 30 years, has difficulties to accept that progenitor cells give rise to new neurons in some specific regions of the mammalian adult brain, the neurogenic niches (Kuhn et al., 1996;Doetsch et al., 1997, 1999).

Why microglia kill neurons after neural disorders? The friendly fire hypothesis

Neuroinflammation plays a fundamental role on the pathophysiology of acute and chronic neural disorders.Microglia activation is a major event following central nervous system inflammation displaying different phenotypes with beneficial and detrimental actions(a Janus face).The reason for this apparent duality is unknown.We have previously shown that following experimental middle cerebral artery occlusion in the rat brain,microglia seem to support and impair adult neurogenesis in the same ischemic striatum.Based on these results,we raised the hypothesis that in the same pathologic environment,gradients of different ligands distributed over different anatomical niches might contribute to both detrimental and beneficial microglial phenotypes.These ligands(“danger signals”)are released by dying cells and bind to microglial receptors in their membranes.Activation of different microglial receptors induces downstream biochemical pathways culminating in a spectrum of microglial phenotypes like M1 and M2 and others.In this paper,we first review the immune functions of microglia and the role of toll-like receptors on the fight against infections.We then briefly revise the dual role of microglia after neural disorders.We then propose a novel hypothesis to explain the Janus face of microglia during the pathophysiology of central nervous system diseases:the“friendly fire hypothesis”.According to this idea“danger signals”or danger associated molecular patterns released by stressed,damaged and/or dying cells during stroke,trauma and other diseases might activate microglial pattern-recognition receptors(i.e.,toll like receptors)or other unidentified receptors normally activated by pathogens.This could activate the same genetic and biochemical machinery used by microglia to fight against pathogens even in the absence of infection.According to this notion,microglia may cause bystander neuronal damage with a kind of blind“friendly fire”,fighting against a non-existing infection during non-infectious disorders,like stroke and trauma.The“friendly fire hypothesis”is a novel proposal to explain why microglia may be detrimental and beneficial after acute and chronic neural disorders and may direct future investigations for developing of neuroprotective agents.