Histone acetylation is a promising target for novel treatments of psychiatric illness due to its control over patterns of gene transcription that ultimately establish and stabilize cognitive and behavioral processes. The current study reveals a robust antidepressant-like effect of HDAC inhibitors delivered directly into the NAc after chronic social defeat stress. Our results also demonstrate that chronic social stress induces a complex pattern of changes in H3 acetylation in the NAc, with a dramatic decrease observed 1 hr after the last stress, followed by a smaller, but sustained increase in acetylated H3 that persists for at least 2 weeks. The observation that inhibition of HDACs and the consequent increase in H3 acetylation in the NAc induces robust antidepressant-like effects suggests that the transient reduction in H3 acetylation after social defeat stress may contribute to depressive symptoms, while the sustained increase in H3 acetylation represents a positive adaptation that serves to restore normal functioning. The mechanism underlying the transient decrease in H3 acetylation remains unknown, but the lasting increase in levels of acetylated H3 in the NAc could be mediated via a persistent and selective decrease in expression of the class I HDAC, HDAC2, in the NAc. The notion that down-regulation of HDAC2 in the NAc may be an adaptive mechanism is interesting in light of recent findings that, in the hippocampus, HDAC2 is an important mediator of synaptic plasticity and morphological changes necessary for associative learning (Guan et al., 2008
). This underscores the very different effects that HDAC2, like many other proteins (Nestler and Carlezon, 2006
), play in distinct brain regions.
Importantly, we show here that human depression, like chronic social defeat in mice, is also associated with increased levels of H3 acetylation and reduced levels of HDAC2 expression in the NAc. These findings further establish the validity of chronic social defeat as a bona fide
model of depression (Kudryavtseva et al., 1991
; Rygula et al., 2005
; Berton et al., 2006
; Krishnan et al., 2007
; Miczek et al., 2008
). Based on the antidepressant-like effects of HDAC inhibition in the mouse NAc, we hypothesize that reduced HDAC2 expression in the NAc is an adaptive neuronal response that emerges with clinical depression. We speculate that this adaptive response may, in some individuals, promote neuronal plasticity and contribute to recovery. The fact that chronic fluoxetine treatment does not increase H3 acetylation, or decrease HDAC2 levels, in the mouse NAc indicates that HDAC inhibition represents a distinct and fundamentally novel mechanism of antidepressant action that now warrants direct study in clinical populations.
The NAc is important for processing reward-related stimuli (Wise, 1987
; Koob, 1996
; Carelli, 2002
). Clinical depression often includes anhedonic, motivational, and arousal deficits, suggesting a role for the NAc in mediating these symptoms (Nestler and Carlezon, 2006
). As such, we find that infusing HDAC inhibitors into the NAc reverses the effect of chronic defeat stress on social avoidance, decreased sucrose preference, and decreased mobility during the forced swim task. The persistent increase in H3 acetylation in this brain area combined with the antidepressant-like effect of HDAC inhibitor infusion verifies the importance of the NAc in the emergence of stress-induced depressive symptoms and their reversal during effective treatment. To complement the behavioral studies, we compared global patterns of gene expression by microarray analysis in the NAc after local MS-275 infusion with that of systemic fluoxetine treatment in stressed and control mice. These gene arrays provide novel insight into potential molecular targets for the development of new treatments for depression, particularly symptoms that pertain to NAc function. Social defeat stress produces a distinct pattern of gene expression, in the NAc, which is generally reversed by treatment with either MS-275 or fluoxetine. For example, the neuropeptide cortistatin is down-regulated by stress in the NAc, an effect reversed by both treatments. Cortistatin is normally regulated by circadian variables, and disruptions in this gene may be related to the severe disruptions in sleep and arousal among depressed individuals (Spier and de Lecea, 2000
). In addition, stress-induced disruption of glutamatergic signaling, synaptic plasticity, inflammatory responses, and chromatin remodeling may serve to promote and sustain depressive-like behaviors: genes such as slc17a
(glutamate transporter protein), abl1
(tyrosine kinase), nrn1
(Ras associated protein 3b), tnfrsf1a
(tumor necrosis factor receptor superfamily, member 1A), and sin3b
(transcriptional regulator), involved in these various molecular pathways, are each regulated by chronic stress and reversed by both drug treatments. Importantly, these genes may be part of a shared mechanism of antidepressant action for MS-275 and fluoxetine.
In an attempt to reveal novel targets for antidepressant action, we examined genes whose regulation by chronic stress was reversed by MS-275, but not by fluoxetine. Examples of such genes include gja5
(involved in gap junction formation) and dlgap1
(assembles postsynaptic density complexes). A decrease in gap junctions after cocaine administration (Bennett et al., 1999
) may indicate a possible mechanism for cross-sensitization between stress and stimulants. Insensitivity to the α-adrenergic receptor (encoded by the gene adra1a
) has been implicated in depression (Cedarbaum and Aghajanian, 1976
), and this gene was also down-regulated by stress and restored by MS-275. Interestingly, the observation that many genes induced by chronic defeat stress were also restored by MS-275 indicates the complexity of transcriptional regulation in the brain. Overall, these results define the complex patterns of gene regulation in the NAc during the emergence of depressive-like symptoms and their reversal by antidepressant treatments.
Depression involves the persistent expression of diverse symptoms, suggesting the involvement of stable molecular adaptations in the NAc, a brain region important for processing emotional stimuli. Here, we report that chronic social stress leads to prolonged increases in levels of acetylated histone H3 in the NAc with a corresponding decrease in levels of HDAC2. The effects of social stress on acetylated H3 and HDAC2 in the current mouse model of depression were also observed in the NAc of postmortem depressed humans, which further validates the social defeat model and demonstrates the relevance of chromatin remodeling in human depression. Furthermore, HDAC inhibitor infusion into the NAc after chronic stress produces robust antidepressant-like effects across several behavioral assays. Presumably, the antidepressant-like effects of HDAC inhibition occur by increasing histone acetylation at certain gene promoters and thereby exerting complex effects on gene expression, as revealed here by gene arrays for MS-275. These effects overlap significantly with those of standard antidepressants but also reveal additional potential targets of HDAC inhibition. Together, these findings support the utility of HDAC inhibitors as antidepressants, and provide novel insight regarding the molecular mechanisms underlying antidepressant responses.