Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleusaccumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the futuredevelopmentofnovelantidepressanttreatments.Together,thesefindingsprovidenewinsightintotheunderlyingmolecularmechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.

In contrast to the vast literature on stress effects on the brain, relatively little is known about the molecular mechanisms of resilience, the ability of some individuals to escape the deleterious effects of stress. Here we show that the transcription factor, ΔFosB, mediates an essential mechanism of resilience in mice. Induction of ΔFosB in the nucleus accumbens, a key brain reward region, in response to chronic social defeat stress is both necessary and sufficient for resilience. ΔFosB induction also is required for the ability of the standard antidepressant, fluoxetine, to reverse behavioral pathology induced by social defeat. ΔFosB produces these effects through the induction of the GluR2 AMPA glutamate receptor subunit, which decreases the responsiveness of nucleus accumbens neurons to glutamate, and through other synaptic proteins. Together, these findings establish a novel molecular pathway underlying both resilience and antidepressant action.

Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry and electrophysiology in a locomotor sensitization paradigm with repeated, daily noncontingent cocaine (15 mg/kg) injections, we show that dominant negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDAR) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here, we show that repeated cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. We show further, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1, or local knockout of Rac1 from floxed Rac1 mice, is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 mutant, or light activation of a photoactivatible form of Rac1, blocks the ability of repeated cocaine to produce this effect. Downregulation of Rac1 activity in nucleus accumbens likewise promotes behavioral responses to cocaine, with Rac1 activation producing the opposite effect. These findings establish an important role for Rac1 signaling in mediating structural and behavioral plasticity to cocaine.

Summary Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to chronic morphine. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain’s reward circuitry.