Abstract
Acute or chronic administrations of high doses of ethanol in mice are known to produce severe cognitive deficits linked to hippocampal damage. However, we recently reported that chronic and moderate ethanol intake in C57BL/6J mice induced chromatin remodeling within the Bdnf promoters, leading to both enhanced brain-derived neurotrophic factor (BDNF) expression and hippocampal neurogenesis under free-choice protocol. We performed here a series of cellular and behavioral studies to analyze the consequences of these modifications. We showed that a 3-week chronic free-choice ethanol consumption in C57BL/6J mice led to a decrease in DNA methylation of the Bdnf gene within the CA1 and CA3 subfields of the hippocampus, and upregulated hippocampal BDNF signaling pathways mediated by ERK, AKT and CREB. However, this activation did not affect long-term potentiation in the CA1. Conversely, ethanol intake impaired learning and memory capacities analyzed in the contextual fear conditioning test and the novel object recognition task. In addition, ethanol increased behavioral perseveration in the Barnes maze test but did not alter the mouse overall spatial capacities. These data suggested that in conditions of chronic and moderate ethanol intake, the chromatin remodeling leading to BDNF signaling upregulation is probably an adaptive process, engaged via epigenetic regulations, to counteract the cognitive deficits induced by ethanol.
Highlights
Drugs of abuse have been shown to alter synaptic plasticity and related neuronal function, and this damage is important in case of alcohol.[1]
In order to further characterize the epigenetic modification induced by chronic free-choice ethanol consumption in C57BL/6J mice and the functional consequences of these ethanol-induced epigenetic regulations, we performed a series of investigations aimed at analyzing DNA methylation within the Bdnf gene and brain-derived neurotrophic factor (BDNF) intracellular pathways that involve the activation of TrkB receptor-dependent kinases
We showed that ethanol consumption decreased DNA methylation within the Bdnf gene in CA1 and CA3 subfields of the hippocampus, upregulated TrkB-dependent BDNF intracellular signaling pathways, but led to some alterations in learning, memory and perseveration behavior
Summary
Drugs of abuse have been shown to alter synaptic plasticity and related neuronal function, and this damage is important in case of alcohol.[1]. In order to further characterize the epigenetic modification induced by chronic free-choice ethanol consumption in C57BL/6J mice and the functional consequences of these ethanol-induced epigenetic regulations, we performed a series of investigations aimed at analyzing DNA methylation within the Bdnf gene and BDNF intracellular pathways that involve the activation of TrkB receptor-dependent kinases. We showed that ethanol consumption decreased DNA methylation within the Bdnf gene in CA1 and CA3 subfields of the hippocampus, upregulated TrkB-dependent BDNF intracellular signaling pathways, but led to some alterations in learning, memory and perseveration behavior. These data suggested that ethanol-induced neuroplasticity involving BDNF signaling pathway could be an adaptive response to the cognitive impairments induced by ethanol intake
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