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      An enriched environment improves maternal sleep deprivation‐induced cognitive deficits and synaptic plasticity via hippocampal histone acetylation

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          Abstract

          Introduction

          Growing evidence clearly demonstrates that maternal rodents exposure to sleep deprivation (SD) during late pregnancy impairs learning and memory in their offspring. Epigenetic mechanisms, particularly histone acetylation, are known to be involved in synaptic plasticity, learning, and memory. We hypothesize that the cognitive decline induced by SD during late pregnancy is associated with histone acetylation dysfunction, and this effect could be reversed by an enriched environment (EE).

          Methods

          In the present study, pregnant CD‐1 mice were exposed to SD during the third trimester of pregnancy. After weaning, all offspring were randomly assigned to two subgroups in either a standard environment or an EE. When offspring were 3 months old, the Morris water maze was used to evaluate hippocampal‐dependent learning and memory ability. Molecular biological techniques, including western blot and real‐time fluorescence quantitative polymerase chain reaction, were used to examine the histone acetylation pathway and synaptic plasticity markers in the hippocampus of offspring.

          Results

          The results showed that the following were all reversed by EE treatment: maternal SD (MSD)‐induced cognitive deficits including spatial learning and memory; histone acetylation dysfunction including increased histone deacetylase 2 (HDAC2) and decreased histone acetyltransferase (CBP), and the acetylation levels of H3K9 and H4K12; synaptic plasticity dysfunction including decreased brain‐derived neurotrophic factor; and postsynaptic density protein‐95.

          Conclusions

          Our findings suggested that MSD could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by EE treatment.

          Abstract

          The study showed that maternal sleep deprivation could damage learning ability and memory in offspring via the histone acetylation pathway. This effect could be reversed by enriched environment treatment

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          Most cited references61

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          The sleep-deprived human brain

          How does sleep deprivation affect the human brain? Walker and colleagues review neuroimaging studies on the consequences of sleep deprivation on cognition and emotion — with specific focuses on attention and working memory, positive and negative emotion, and hippocampal learning — and the mechanisms underlying these effects.
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            Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate

            Exercise induces beneficial responses in the brain, which is accompanied by an increase in BDNF, a trophic factor associated with cognitive improvement and the alleviation of depression and anxiety. However, the exact mechanisms whereby physical exercise produces an induction in brain Bdnf gene expression are not well understood. While pharmacological doses of HDAC inhibitors exert positive effects on Bdnf gene transcription, the inhibitors represent small molecules that do not occur in vivo. Here, we report that an endogenous molecule released after exercise is capable of inducing key promoters of the Mus musculus Bdnf gene. The metabolite β-hydroxybutyrate, which increases after prolonged exercise, induces the activities of Bdnf promoters, particularly promoter I, which is activity-dependent. We have discovered that the action of β-hydroxybutyrate is specifically upon HDAC2 and HDAC3, which act upon selective Bdnf promoters. Moreover, the effects upon hippocampal Bdnf expression were observed after direct ventricular application of β-hydroxybutyrate. Electrophysiological measurements indicate that β-hydroxybutyrate causes an increase in neurotransmitter release, which is dependent upon the TrkB receptor. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF. DOI: http://dx.doi.org/10.7554/eLife.15092.001
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              HDAC2 negatively regulates memory formation and synaptic plasticity

              Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wildtype mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACi requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not HDAC1, reduced dendritic spine density, synapse number, synaptic plasticity, and memory formation. Conversely, HDAC2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic HDACi treatment in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic HDACi treatment. Correspondingly, HDACi treatment failed to further facilitate memory formation in HDAC2-deficient mice. Furthermore, analysis of promoter occupancy revealed association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Together, our results suggest that HDAC2 plays a role in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.
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                Author and article information

                Contributors
                doctorcgh@163.com
                984966161@qq.com
                Journal
                Brain Behav
                Brain Behav
                10.1002/(ISSN)2157-9032
                BRB3
                Brain and Behavior
                John Wiley and Sons Inc. (Hoboken )
                2162-3279
                18 April 2023
                June 2023
                : 13
                : 6 ( doiID: 10.1002/brb3.v13.6 )
                : e3018
                Affiliations
                [ 1 ] Department of Neurology (Sleep Disorders) the Affiliated Chaohu Hospital of Anhui Medical University Hefei Anhui P. R. China
                Author notes
                [*] [* ] Correspondence

                Gui‐Hai Chen, Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, Anhui Province, P. R. China.

                Email: doctorcgh@ 123456163.com

                Xue‐Yan Li, Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei 238000, Anhui Province, P. R. China,

                Email: 984966161@ 123456qq.com

                Author information
                https://orcid.org/0000-0002-1021-8340
                Article
                BRB33018
                10.1002/brb3.3018
                10275536
                37073496
                bc08ec97-8f26-49a9-a1d7-89a5abbe5d48
                © 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 March 2023
                : 05 December 2022
                : 02 April 2023
                Page count
                Figures: 5, Tables: 1, Pages: 11, Words: 7196
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Award ID: 81671316
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                June 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.9 mode:remove_FC converted:16.06.2023

                Neurosciences
                enriched environment,histone acetylation,learning and memory,maternal sleep deprivation

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