Abstract
There is collecting evidence suggesting that the process of chromatin remodeling such as changes in histone acetylation contribute to the formation of stress-related memory. Recently, the ventrolateral orbital cortex (VLO), a major subdivision of orbitofrontal cortex (OFC), was shown to be involved in antidepressant-like actions through epigenetic mechanisms. Here, we further investigated the effects of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) on stress-related memory formation and the underlying molecular mechanisms by using the traditional two-day forced swimming test (FST). The results showed that VPA significantly increased the immobility time on day 2 when infused into the VLO before the initial forced swim stress on day 1. The learned immobility response to the stress was associated with increased phosphorylation of extracellular signal-regulated kinase (ERK) in VLO and hippocampus on the first day. The levels of phosphorylated ERK (phospho-ERK) in VLO and hippocampus were significantly decreased when retested 24 h later. The pretreatment with intra-VLO VPA infusion further reduced the activation of ERK on day 2 and day 7 compared with the saline controls. Moreover, the VPA infusion pretreatment also induced a significantly decreased BDNF level in the VLO on day 2, whereas no change was detected in the hippocampus. These findings suggest that VPA enhance the memories of emotionally stressful events and the ERK activity is implicated in stimulating adaptive and mnemonic processes in case the event would recur.
Highlights
Stressful events are associated with many psychological disorders, most notably major depression and posttraumatic stress disorder [1,2]
Since mitogen-activated protein kinase phosphatase-1 (Mkp-1) is capable of inactivating extracellular signalregulated kinase (ERK) [12], it is conceivable that valproic acid (VPA) might affect the acquired immobility response through ERK signaling pathway in the ventrolateral orbital cortex (VLO)
Since VPA is a potent GABAergic signaling enhancer besides a histone deacetylase inhibitor (HDACi), we further investigated the effect of valpromide (VPM) that enhance GABAergic signaling but not alter HDAC activity on the immobility time during the two-day forced swimming test (FST) injected into the VLO before the initial forced swim stress on day 1
Summary
Stressful events are associated with many psychological disorders, most notably major depression and posttraumatic stress disorder [1,2]. The ventrolateral orbital cortex (VLO), a major subdivision of orbitofrontal cortex (OFC), is well known to be involved in nociception [4,5] This brain area has received considerable attentions for its role in antidepressant response in animal models such as forced swimming test (FST) [6,7]. The immobility response observed 24 h later after the initial test in rat can be viewed as an adaptive learning response to stress [8]. The encoding of these stressful memories requires chromatin remodeling such as histone H3 phosphorylation and acetylation in dentate gyrus granule neurons [9]. Since Mkp-1 is capable of inactivating extracellular signalregulated kinase (ERK) [12], it is conceivable that VPA might affect the acquired immobility response through ERK signaling pathway in the VLO
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