title: Evidence for the contribution of adult neurogenesis and hippocampal cell death in experimental cerebral malaria cognitive outcome.
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.
authors.affiliation: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Neuroscience Branch, Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: mirandas.aline@gmail.com.
authors.forename: A S
authors.initials: AS
authors.lastname: de Miranda
authors.affiliation: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: F
authors.initials: F
authors.lastname: Brant
authors.affiliation: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: A C
authors.initials: AC
authors.lastname: Campos
authors.affiliation: Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: L B
authors.initials: LB
authors.lastname: Vieira
authors.affiliation: Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Neuroscience Branch, Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Department of Pharmacology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: N P
authors.initials: NP
authors.lastname: Rocha
authors.affiliation: Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: D
authors.initials: D
authors.lastname: Cisalpino
authors.affiliation: National Institute of Science and Technology in Molecular Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: N S
authors.initials: NS
authors.lastname: Binda
authors.affiliation: Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Neuroscience Branch, Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: D H
authors.initials: DH
authors.lastname: Rodrigues
authors.affiliation: Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: F S
authors.initials: FS
authors.lastname: Machado
authors.affiliation: Department of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: Postgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Immunopharmacology Group, Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil; Neuroscience Branch, Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. Electronic address: altexr@gmail.com.
authors.forename: A L
authors.initials: AL
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D005260:Female; D005625:Frontal Lobe / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D016779:Malaria, Cerebral / Q000473:pathology / Q000503:physiopathology*; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D055495:Neurogenesis / Q000502:physiology*; D010962:Plasmodium berghei; D012333:RNA, Messenger / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D012333:RNA, Messenger; D020813:Receptor, trkB
keywords: CCL11; cerebral malaria; cognitive dysfunction; cytokines; neuroinflammation; neurotrophin