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Mentions: Results of the associative learning experiments, expressed as nose-poke durations at the end of the rewarded stimulus for the anticipation of the reward (CS+), are shown in Figure 2. Values for the CS− control group remained close to baseline and are therefore not illustrated. Mean nose-poke durations increased between sessions in all groups. It took more sessions for the untreated NVHL group to learn that the cue predicted food. Administering phenylbutyrate had no effect on the learning process in the sham-operated groups of rats. NVHL rats treated with phenylbutyrate attained a steady level that was higher than that attained by vehicle-injected NVHL rats, and in fewer sessions. The two criteria for adequate learning were statistically met: there was a difference according to the whether or not food was announced by the stimulus [CS+ vs. CS−: F(1,32) = 63.8, p < 0.0001], and a progression was observed from session to session [F(7,224) = 21.0, p < 0.0001]. The global effect of the lesion was significant [F(1,32) = 7.06, p < 0.05) and interacted with the effect of treatment [F(1,32) = 5.03, p < 0.05). This is evidence that the treatment was more or only efficient in NVHL rats, as seen in Figure 2. Interaction between the effect of the lesion and the changes between the sessions was also significant [F(7,224) = 2.81, p < 0.01), which indicates that the learning process did not follow the same timeline in lesioned rats as in their sham-operated controls. It is noteworthy that the mean final performance of non-treated NVHL rats was not as good as the other groups. This had been already observed previously (Macedo et al., 2008).
The HDAC Inhibitor Phenylbutyrate Reverses Effects of Neonatal Ventral Hippocampal Lesion in Rats
Bottom Line: In contrast, NVHL rats' hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment.Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition.This represents a novel approach for treating disorders resulting from insults occurring during brain development.
Affiliation: U666 INSERM, Faculté de Médecine, Université de Strasbourg Strasbourg, France.
Abstract: Recent evidence suggests that epigenetic mechanisms play a role in psychiatric diseases. In this study, we considered rats with neonatal ventral hippocampal lesions (NVHL) that are currently used for modeling neurodevelopmental aspects of schizophrenia. Contribution of epigenetic regulation to the effects of the lesion was investigated, using a histone deacetylase (HDAC) inhibitor. Lesioned or sham-operated rats were treated with the general HDAC inhibitor phenylbutyrate, which was injected daily from the day after surgery until adulthood. Changes in the volume of the lesion were monitored by magnetic resonance imaging (MRI). Anxiety was analyzed in the Plus Maze Test. Hypersensitivity of the dopaminergic system was evaluated by measuring the locomotor response to apomorphine. An associative conditioning test rewarded with food was used to evaluate learning abilities. The volume of the lesions expanded long after surgery, independently of the treatment, as assessed by MRI. Removal of the ventral hippocampus reduced anxiety, and this remained unchanged when animals were treated with phenylbutyrate. In contrast, NVHL rats' hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment. Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition. The study provides evidence that chromatin remodeling may be useful for limiting behavioral consequences due to lesioning of the ventral hippocampus at an early age. This represents a novel approach for treating disorders resulting from insults occurring during brain development.
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