Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment - PubMed (original) (raw)

Reversal of deficits in dendritic spines, BDNF and Arc expression in the amygdala during alcohol dependence by HDAC inhibitor treatment

Chang You et al. Int J Neuropsychopharmacol. 2014 Feb.

Abstract

Development of anxiety-like behaviours during ethanol withdrawal has been correlated with increased histone deacetylase (HDAC) activity and decreased brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated protein (Arc) gene expression in the amygdala. Furthermore, HDAC-mediated histone modifications play a role in synaptic plasticity. In this study we used the HDAC inhibitor trichostatin A (TSA) to determine whether HDAC inhibition could prevent ethanol withdrawal-induced deficits in dendritic spine density (DSD), BDNF or Arc expression in the amygdala of rats. It was found that decreased BDNF and Arc expression in the central (CeA) and medial nucleus of amygdala (MeA), observed during withdrawal after chronic ethanol exposure, were normalized following acute TSA treatment. TSA treatment was also able to attenuate anxiety-like behaviours during ethanol withdrawal and correct the observed decrease in DSD in the CeA and MeA of ethanol-withdrawn rats. Taken together, these findings demonstrate that correcting the deficits in histone acetylation through TSA treatment also amends downstream synaptic plasticity-related deficits such as BDNF and Arc expression, and DSD in the CeA and MeA as well as attenuates anxiety-like behaviours in rats during withdrawal after chronic ethanol exposure.

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Conflict of interest statement

Conflict of Interest

SCP reports that a US patent application on a related topic (serial number 60/848237 filed on September 29th, 2006) is currently pending. All other authors reported no biomedical financial interests or potential conflicts of interest.

Figures

Figure 1

Figure 1

Measurement of anxiety-like behaviors using the elevated plus maze (EPM) shows increased anxiety levels in ethanol-withdrawn rats and attenuation of anxiety-like behaviors following TSA treatment. The anxiety-like behaviors are represented by open arm and closed arm activity. Values are the mean ± SEM of 6–8 rats in each group. * Significantly different (p < 0.001; one-way ANOVA followed by post hoc analysis by Tukey’s test; percentage of open arm entries [_F_4, 27=21.25, p<.001] and the percentage of time spent in the open arms [_F_4, 27=17.141, p<.001]) from all other groups (Control+ Vehicle, Ethanol+ Vehicle, Withdrawal+ TSA, Control+ TSA injected rats).

Figure 2

Figure 2

Measurement of anxiety-like behaviors in rats using light/dark box (LDB) shows increased anxiety levels in ethanol-withdrawn rats. TSA treatment prevents the withdrawal-induced anxiogenic effect. The data are represented as percentage of time spent in light and dark compartment of LDB. The general activities of the rats are measured by total ambulations during the exploration of LDB. Values are the mean ± SEM of 6–7 rats in each group. * Significantly different (p < 0.001; one-way ANOVA followed by post hoc analysis by Tukey’s test; percentage of time spent in the light and dark compartments [_F_4, 26=43.71, p<.001]) from all other groups (Control+ Vehicle, Ethanol+ Vehicle, Withdrawal+ TSA, Control+ TSA injected rats). # Groups significantly different (p<0.001) from each other.

Figure 3

Figure 3

A, Representative photomicrographs of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated (Arc) protein gold-immunolabeling and Arc mRNA in situ RT-PCR in the central nucleus of amygdala (CeA) of various rat groups (Scale bar = 40 μm). B, Bar diagram showing the effects of chronic ethanol treatment and its withdrawal (with or without TSA treatment) on BDNF protein, Arc protein and mRNA levels in CeA, medial nucleus of amygdala (MeA) and basolateral amygdala (BLA) of rats. Values are mean ± SEM of 6 rats in each group. * Significantly different (p <0.001; one-way ANOVA followed by post hoc analysis by Tukey’s test; [BDNF protein: CeA, _F_4,25=109.11 , p<.001; MeA, _F_4,25=100.51 , p<.001; Arc protein: CeA, _F_4,25=60.23, p<.001; MeA, _F_4,25=29.93, p<.001; Arc mRNA: CeA, _F_4,25=25.59, p<.001; MeA, _F_4,25=16.24, p<.001]) from all other groups (Control+ Vehicle, Ethanol+ Vehicle, Withdrawal+ TSA, Control+ TSA injected rats).

Figure 3

Figure 3

A, Representative photomicrographs of brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton-associated (Arc) protein gold-immunolabeling and Arc mRNA in situ RT-PCR in the central nucleus of amygdala (CeA) of various rat groups (Scale bar = 40 μm). B, Bar diagram showing the effects of chronic ethanol treatment and its withdrawal (with or without TSA treatment) on BDNF protein, Arc protein and mRNA levels in CeA, medial nucleus of amygdala (MeA) and basolateral amygdala (BLA) of rats. Values are mean ± SEM of 6 rats in each group. * Significantly different (p <0.001; one-way ANOVA followed by post hoc analysis by Tukey’s test; [BDNF protein: CeA, _F_4,25=109.11 , p<.001; MeA, _F_4,25=100.51 , p<.001; Arc protein: CeA, _F_4,25=60.23, p<.001; MeA, _F_4,25=29.93, p<.001; Arc mRNA: CeA, _F_4,25=25.59, p<.001; MeA, _F_4,25=16.24, p<.001]) from all other groups (Control+ Vehicle, Ethanol+ Vehicle, Withdrawal+ TSA, Control+ TSA injected rats).

Figure 4

Figure 4

A, Representative photomicrographs of dendritic spines in the central nucleus of amygdala (CeA) and basolateral amygdala (BLA) of various rat groups as measured by Golgi-Cox staining (scale bar = 10 μm). B, Effect of chronic ethanol treatment and its withdrawal (with or without TSA treatment) on dendritic spine density in the amygdaloid brain regions of rats. Values are mean ± SEM of 6 rats in each group. *Significantly different [p <0.001; one-way ANOVA followed by post hoc analysis by Tukey’s test; CeA, _F_4, 25=14.89, p<.001; Medial nucleus of amygdala (MeA), _F_4, 25=13.51, p<.001] from all other groups (Control+ Vehicle, Ethanol+ Vehicle, Withdrawal+ TSA, Control+ TSA injected rats).

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