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Effects of Physical Exercise on Adult Hippocampal Neurogenesis: Changes in DNA Methylation and a Focus on Smad2 Gene
Author(s) -
Trejo Jose Luis,
Herrera Antonio,
FontánLozano Ángela,
Pons Sebastián,
Gradari Simona
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb40
Subject(s) - neurogenesis , dentate gyrus , dna methylation , hippocampal formation , biology , gene expression , hippocampus , gene knockdown , gene silencing , epigenetics , neuroscience , methylation , gene , genetics
Physical activity is an important factor capable of inducing changes in the brain. This study aims to investigate if the expression of certain genes is regulated by changes in the DNA methylation in the hippocampus of the adult mouse, in response to exercise. In particular, the research has focused on the Smad2 gene, manipulating its expression in the dentate gyrus with lentiviral vectors, and studying its role during the process of neurogenesis. First of all, the hippocampus regions from sedentary and runner animals were analyzed using a microarray detecting the DNA methylation status of 24 transcription factors, and then gene expression was assessed by means of a qPCR. Lentiviral vectors were therefore created to over‐express Smad2, or to silence it by means of a shRNA. Afterward s , mice were subjected to bilateral stereotactic injections into the dentate gyrus to inoculate the different kind of lentivirus. Half of the animals from each group remained in their cage for the duration of the experiment, while the other half undertook physical exercise for two weeks. Finally, animals performed behavioural tests to assess activity, state of anxiety and ability in spatial learning and memory. Neurogenesis and modifications in synaptic plasticity were analyzed in the granule neurons with immunohistochemistry techniques. Results show that exercise induces changes in the DNA methylation and it regulates the expression of many transcription factors, such as Smad2. The silencing and over‐expression studies elucidate a role for this gene in the late‐stages of adult hippocampal neurogenesis: Smad2 does not promote cell proliferation and survival but it induces neuron's maturation and differentiation. Moreover, Smad2 silencing compromises the spatial learning abilities in sedentary mice, while exercise is able to reverse the impairments due to the genetic manipulations. This study confirms that exercise alters DNA methylation, it has a role in neural plasticity and, moreover, that Smad2 is involved in the late‐stages of hippocampal neurogenesis. Support or Funding Information Grant BFU2013‐48907‐R from Ministerio de Economía y Competitividad, Spain