Named Series: Neurogenesis and InflammationNeurogenesis, inflammation and behavior
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► New neurons are continuously produced in two regions of the adult brain, the hippocampus and the olfactory bulb. This review discusses current understanding of how the immune system affects adult neurogenesis and the implications for cognitive function.
Section snippets
Introduction to adult neurogenesis
Before the 1990s, it was widely thought that neurons in the adult human brain did not regenerate. Consequently, it was thought that if neurons died during your adult life for any reason (e.g., oxidative stress, stroke, neurodegenerative disease, head trauma, normal aging), they would never be replaced. However, in the 1960s, Altman and colleagues challenged this idea, reporting that new neurons are continuously and spontaneously born in at least two regions of the adult rat brain: the
Neuroinflammation
The immune system can be divided into the innate and adaptive immune systems. While these divisions work together to orchestrate the immune response each serves distinct roles that facilitate recovery from an injury or infection. The innate immune system serves as the initial defensive to combat an infection. This response is rapid, but non-specific and is primarily mediated by cells of a myeloid origin (i.e., macrophages, neutrophils, and dendritic cells). In contrast the adaptive branch of
Phenotype-specific effects of microglia on hippocampal neurogenesis
Microglia can have both supportive and harmful effects on adulthood neurogenesis depending on their state of activation. Microglia that express a proinflammatory phenotype generally impair neurogenesis whereas as microglia that express a neuroprotective phenotype can facilitate new cell survival. The present section will cover the differential phenotypes microglia express and the distinct effects each phenotype has on influencing hippocampal neurogenesis.
Role of microglia in activity-induced increases in neurogenesis
As discussed, neurogenesis is regulated by a variety of factors. Exercise has been consistently shown to enhance hippocampal neurogenesis by increasing neuronal differentiation and new cell survival. Though the data are limited, there is reason to speculate that immune cells may participate in the enhancement of neurogenesis following exercise and environmental enrichment. For example, Ziv et al. (2006) report that interactions between T-cells and microglia participate in the environmental
Role of microglia in age-related decline in neurogenesis
Hippocampal neurogenesis persists throughout an individual’s life, as centurions show evidence of neurogenesis (Knoth et al., 2010). However, there is a substantial decline in neurogenesis with normal aging. Aging is associated with a decrease in both proliferation and survival of new cells (Blackmore et al., 2009, Kohman et al., 2011, van Praag et al., 2005). Several factors likely contribute to the age-related decrease in neurogenesis. For instance, neural progenitor cells have been reported
Potential role of neurogenesis in inflammation-induced cognitive deficits
Activation of the immune system leads to a host of well characterized behavioral changes, some of which are adaptive responses that facilitate recovery and others less so. Sickness behavior is a constellation of behavioral alterations that include a decrease in locomotion, social and sexual behavior, development of anorexia and a fever response (Dantzer, 2004). These behavioral changes are thought to reflect an altered motivation state rather than a physical disability and expedite recovery
Conclusion
The evidence clearly indicates that neuroinflammation can suppress hippocampal neurogenesis. However, we are just beginning to understand the role microglia play in regulating neurogenesis under basal conditions in the absence of an infection or injury. Clearly, microglia are not simply waiting around in the brain for an infection to occur, but rather are participating in basal neural processes, such as neurogenesis. Progress in research has created a broader view of microglia’s role within the
Funding
Supported by Grants from National Institute of Health, MH083807 and DA027487 to J.S.R and from National Institute on Aging K99AG0404184 to R.A.K.
References (133)
- et al.
Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain
Brain Res. Dev. Brain Res.
(1999) - et al.
Learning may reduce neurogenesis in adult rat dentate gyrus
Neurosci. Lett.
(2004) - et al.
Insulin-like growth factor-I and neurogenesis in the adult mammalian brain
Brain Res. Dev. Brain Res.
(2002) - et al.
Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats
Neurobiol. Aging
(2011) - et al.
Involvement of cyclooxygenase-2 in lipopolysaccharide-induced impairment of the newborn cell survival in the adult mouse dentate gyrus
Neuroscience
(2008) - et al.
Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks
Brain Behav. Immun.
(2012) - et al.
Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain
Neurosci. Lett.
(2000) - et al.
Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells
Mol. Cell. Neurosci.
(2006) - et al.
Induction of c-Fos, Zif268, and Arc from acute bouts of voluntary wheel running in new and pre-existing adult mouse hippocampal granule neurons
Neuroscience
(2011) - et al.
Intact neurogenesis is required for benefits of exercise on spatial memory but not motor performance or contextual fear conditioning in C57BL/6J mice
Neuroscience
(2008)
Prenatal stress diminishes neurogenesis in the dentate gyrus of juvenile rhesus monkeys
Biol. Psychiatry
Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro
Neurosci. Lett.
Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity
Eur. J. Pharmacol.
GABA excitation in the adult brain: a mechanism for excitation–neurogenesis coupling
Neuron
Excitation–neurogenesis coupling in adult neural stem/progenitor cells
Neuron
Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function
Neuroscience
MRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Neurobiol. Aging
IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats
Brain Behav. Immun.
Lipopolysaccharide acutely inhibits proliferation of neural precursor cells in the dentate gyrus in adult rats
Brain Res.
Neurogenesis in adulthood: a possible role in learning
Trends Cogn. Sci.
A role for interleukin-1beta in determining the lineage fate of embryonic rat hippocampal neural precursor cells
Mol. Cell. Neurosci.
Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats
Brain Behav. Immun.
Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice
Brain Behav. Immun.
Protection of hippocampal neurogenesis from toll-like receptor 4-dependent innate immune activation by ablation of prostaglandin E2 receptor subtype EP1 or EP2
Am. J. Pathol.
The neurogenic reserve hypothesis: what is adult hippocampal neurogenesis good for?
Trends Neurosci.
Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: role of Hes1
Mol. Cell. Neurosci.
Angiogenesis but not neurogenesis is critical for normal learning and memory acquisition
Neuroscience
Alleviation of the effects of endotoxin exposure on behavior and hippocampal IL-1beta by a selective non-peptide antagonist of corticotropin-releasing factor receptors
Brain Behav. Immun.
Peripheral bacterial endotoxin administration triggers both memory consolidation and reconsolidation deficits in mice
Brain Behav. Immun.
In animal models, psychosocial stress-induced (neuro)inflammation, apoptosis and reduced neurogenesis are associated to the onset of depression
Prog. Neuropsychopharmacol. Biol. Psychiatry
Lifelong corticosterone level determines age-related decline in neurogenesis and memory
Neurobiol. Aging
Age and gender effects on microglia and astrocyte numbers in brains of mice
Brain Res.
Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning
Brain Behav. Immun.
Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation
Neurobiol. Aging
Local self-renewal can sustain CNS microglia maintenance and function throughout adult life
Nat. Neurosci.
Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb
J. Comp. Neurol.
Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats
J. Comp. Neurol.
Absent or low rate of adult neurogenesis in the hippocampus of bats (Chiroptera)
PLos One
Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage
Eur. J. Neurosci.
The insulin-like growth factor (IGF) receptor type 1 (IGF1R) as an essential component of the signalling network regulating neurogenesis
Mol. Neurobiol.
Identification of astrocyte-expressed factors that modulate neural stem/progenitor cell differentiation
Stem Cells Dev.
Neurogenic niche modulation by activated microglia: transforming growth factor beta increases neurogenesis in the adult dentate gyrus
Eur. J. Neurosci.
Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer’s disease
Neurodegener. Dis.
Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice
Stem Cells
Adult-born hippocampal neurons promote cognitive flexibility in mice
Hippocampus
In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia
Glia
Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus
J. Comp. Neurol.
Control of microglial neurotoxicity by the fractalkine receptor
Nat. Neurosci.
New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks
Hippocampus
Functional analysis of neurovascular adaptations to exercise in the dentate gyrus of young adult mice associated with cognitive gain
Hippocampus
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