Belarbi K, Arellano C, Ferguson R, Jopson T, Rosi S. Chronic neuroinflammation impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Brain Behav Immun 26: 18-23

Brain and Spinal Injury Center, University of California, San Francisco, CA, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 07/2011; 26(1):18-23. DOI: 10.1016/j.bbi.2011.07.225
Source: PubMed


Growing evidence suggests that adult-born granule cells integrate into hippocampal networks and are required for proper cognitive function. Although neuroinflammation is involved in many disorders associated with cognitive impairment, it remains unknown whether it impacts the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Under similar behavioral conditions, exploration-induced expression of the immediate-early gene Arc in hippocampal cells has been linked to cellular activity observed by electrophysiological recording. By detecting exploration-induced Arc protein expression, we investigated whether neuroinflammation alters the recruitment of adult-born neurons into behaviorally relevant hippocampal networks. Neuroinflammation was induced in rats by intra-cerebroventricular infusion of lipopolysaccharide for 28 days. Animals received bromodeoxyuridine injections starting on day 29 (5 days) and were euthanized two months later. Persistent lipopolysaccharide-induced neuroinflammation was reliably detected by microglial activation in the hippocampus. Neuroinflammation did not impact the number of adult-born neurons but did alter their migration pattern through the granule cell layer. There was a positive correlation between the density of activated microglia and alterations in the fraction of existing granule neurons expressing Arc, suggesting that neuroinflammation induced a long-term disruption of hippocampal network activity. The proportion of adult-born neurons expressing behaviorally induced Arc was significantly lower in lipopolysaccharide-treated rats than in controls. This observation supports the fact that neuroinflammation significantly impacts adult-born neurons recruitment into hippocampal networks encoding spatial information.

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    • "Although electrophysiological or optogenetics approaches will be needed to demonstrate the newborn granule neuron- CA2 functional connectivity and whether these connections could affect hippocampal behavior, these experiments provide further confirmation of their existence and possibility of function. Indeed, our data suggest that both neuroprotective and deleterious stimuli modulate this connection simultaneously to both AHN and hippocampal-dependent memory regulation (Belarbi et al., 2012; Cassilhas et al., 2012). Our findings reveal a novel mechanism of hippocampal plasticity, which may have important functional and behavioral consequences. "
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    ABSTRACT: Newborn neurons are continuously added to the hippocampal dentate gyrus (DG) throughout life. Mature and immature granule neurons are believed to send their axonal projections exclusively to the hippocampal CA3 field. However, recent data point to an alternative trisynaptic circuit, involving a direct axonal projection from mature granule neurons to the CA2 field. Whether this circuit takes place only in mature granule neurons or, on the contrary, whether immature granule neurons also contribute to this novel connection is unknown. We used various retroviral vectors to show that immature granule neurons send axonal processes to and establish synaptic contacts with CA2 pyramidal neurons and that axonal growth follows a similar time course to that described for CA3 innervation. In addition, we provide experimental evidence demonstrating that the pathway connecting newborn granule neurons and the CA2 field can be modulated by physiological and deleterious stimuli.
    Experimental Neurology 01/2015; 263. DOI:10.1016/j.expneurol.2014.10.021 · 4.70 Impact Factor
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    • "Conditions stimulating cell proliferation enhance the number of early postmitotic cells in the DG (Brandt et al., 2003), affecting mainly the septal part. Innate neuroinflammation due to experimental allergic encephalomyelitis (EAE) or lipopolysaccharide (LPS)-induced, enhance the proliferation of NPCs in DG (Ekdahl et al., 2003,2009; Das and Basu, 2008; Pluchino et al., 2008; Huehnchen et al., 2011; Voloboueva and Giffard, 2011; Belarbi et al., 2012; Giannakopoulou et al., 2013), being more intense in the septal DG. Although the exact molecular mechanisms that regulate NPCs proliferation and differentiation are largely unknown, several factors have been shown to affect DG neurogenesis. "
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    ABSTRACT: A bulk of evidence currently suggests that hippocampal formation is a heterogeneous brain structure. Most recent studies recognize a hippocampal pole (dorsal/septal or posterior in humans) which is primarily related with memory and learning processes, and another one (ventral/temporal or anterior in humans) which is linked with anxiety, affective or emotional processes. An intermediate region separating the two poles appears to have overlapping characteristics with its neighbors. The present chapter summarizes previously reported differences between septal and temporal dentate gyrus, a key component of the hippocampal circuitry, and provides new information on the segmental variation of the dentate gyrus. Data on the cellular (neuronal and glial) composition of the dentate gyrus are linked with the diverged embryonic origin and continuous cell generation capacity of the septal and temporal poles, septo-temporal molecular/genomic patterns are correlated with trends reported by connectivity (tracing) studies, and distinct characteristics of the two poles in the healthy and the diseased brain are examined together with their peculiar neurochemical and vascularization patterns in order to i. provide an explanatory framework for the understanding of the segmental hippocampal functional and behavioral specialization, and ii. highlight the need for thorough and detailed knowledge of all possible parameters which may allow unlocking of the hippocampal dysfunction. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.
    Dentate Gyrus, Edited by Zackery Lowes, 01/2015: chapter 5: pages 137-198; Nova Science Publishers Inc.., ISBN: 978-1-63463-371-0
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    • "It has been reported that the immune system, among other factors, can regulate neurogenesis. Overexpression of inflammatory mediators, including cytokines and chemokines, promotes a deleterious effect on adult neurogenesis by inhibiting new neuron survival, proliferation, differentiation and integration in preexisting neuronal networks (Bastos et al., 2008; Jakubs et al., 2008; Fujioka and Akema, 2010; Belarbi et al., 2012). On the other hand, it has been suggested that anti-inflammatory cytokines like interleukin 4 (IL-4) and interleukin 10 (IL-10) could play a role in memory and learning processes at least in part by enhancing adult neurogenesis (Butovsky et al., 2006; Derecki et al., 2010). "
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    ABSTRACT: Cognitive dysfunction is a major sign of cerebral malaria (CM). However, the underlying mechanisms of CM cognitive outcome remain poorly understood. A body of evidence suggests that adult neurogenesis may play a role in learning and memory processes. It has also been reported that these phenomena can be regulated by the immune system. We hypothesized that memory dysfunction in CM results from hippocampal neurogenesis impairment mediated by the deregulated immune response during the acute phase of CM. C57Bl/6 mice were infected with Plasmodium berghei ANKA (PbA) strain, using a standardized inoculation of 10(6) parasitized erythrocytes. Long-term working memory was evaluated using the novel object recognition test. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-receptor-kinase (TRK-B) and nerve growth factor (NGF) in the frontal cortex and hippocampus was estimated by real-time polymerase chain reaction (PCR). The protein levels of cytokine interleukin-2 (IL-2), IL-4, IL-6, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and CCL11 and neurotrophins BDNF and NGF were determined using a cytometric bead array (CBA) kit or enzyme-linked immunosorbent assay. Cell viability in the hippocampus was analyzed by Confocal Microscopy. Neurogenesis in the dentate gyrus was determined through quantification of doublecortin (DCX) positive cells. PbA-infected mice presented working memory impairment on day 5 post-infection. At this same time point, CM mice exhibited a decrease in DCX-positive cells in the dentate gyrus in parallel with increased cell death and elevated inflammatory cytokines (IL-6, TNF-α, IFN-γ and CCL11) in the hippocampus and frontal cortex. A significant reduction of BDNF mRNA expression was also found. IL-6 and TNF-α correlated negatively with BDNF and NGF levels in the hippocampus of CM mice. In summary, we provide further evidence that neuroinflammation following PbA-infection influences neurotrophin expression, impairs adult hippocampal neurogenesis and increases hippocampal cell death in association with memory impairment following CM course. The current study identified potential mediators of memory impairment in CM. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 11/2014; 284C:920-933. DOI:10.1016/j.neuroscience.2014.10.062 · 3.36 Impact Factor
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