, 1991, Krishnan et al., 1992, Drevets et al., 1992 and Mayberg et al., 2000). Deep brain stimulation procedures targeting the NAc and its efferent connections in the VTA have shown good therapeutic efficacy in treatment resistant depression (T. Schlaepfer, personal communication). However, it is currently unknown how these stimulation protocols affect NAc microcircuitry and whether they indirectly stimulate fibers of passages that synapse outside

the NAc. Numerous epigenetic and transcriptional mechanisms in mesocorticolimbic reward circuitry underlie antidepressant action and resilient behavioral responses to chronic stress. The transcription factor ΔFosB is upregulated in the NAc of resilient mice following CSDS in a serum response factor (SRF) dependent manner, and genetic overexpression or antagonism NVP-AUY922 solubility dmso of ΔFosB expression promotes behavioral resilience or susceptibility,

respectively (Vialou et al., 2010a and Vialou et al., 2010b). Furthermore, ΔFosB levels are reduced in postmortem NAc samples of human depressed patients. Chronic fluoxetine treatment enhances ΔFosB concentration in the mouse NAc, and ΔFosB is required for fluoxetine-mediated antidepressant effects in susceptible mice. ΔFosB exerts its pro-resiliency effects through its transcriptional targets, including AMPA glutamate receptor subunit GluA2 and Sparc-like 1 (SC1). Following selleck kinase inhibitor CSDS, resilient mice show greater NAc expression of GluA2 than do control or susceptible mice, an effect mediated by ΔFosB binding to the GluA2 promoter. ΔFosB-mediated enhanced GluA2 expression DNA ligase promotes resilience by decreasing AMPA function—GluA2-containing

AMPA receptors are Ca2+ impermeable with lower receptor conductance and reduced inwardly rectifying currents. In addition, SC1, a protein localized to the PSD and necessary for proper synapse assembly, is upregulated both in mice overexpressing ΔFosB and in mice resilient to CSDS. SC1 overexpression reverses social avoidance behavior following CSDS. Epigenetic regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) has been shown by our laboratory to mediate susceptibility vs. resilience to CSDS (Golden et al., 2013). Rac1 is a Rho GTPase involved in the organization and maintenance of the actin cytoskeleton, largely through regulation of its downstream target cofilin, an actin severing protein critically involved in synaptic plasticity. Following CSDS, Rac1 was downregulated in the NAc of susceptible, but not resilient, mice, and its expression correlated with social avoidance behavior. Viral-mediated overexpression and knockdown experiments demonstrated that Rac1 is necessary and sufficient for the expression of resilient behavior following CSDS.