The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ⌬FosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ⌬FosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ⌬FosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ⌬FosB transcriptional activity by expressing ⌬JunD (a negative modulator of ⌬FosB transcriptional function) or to overexpress ⌬FosB, we demonstrate that HPC ⌬FosB regulates learning and memory. Specifically, ⌬JunD expression in HPC impaired learning and memory on a battery of hippocampaldependent tasks in mice. Similarly, general ⌬FosB overexpression also impaired learning. ⌬JunD expression in HPC did not affect anxiety or natural reward, but ⌬FosB overexpression induced anxiogenic behaviors, suggesting that ⌬FosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ⌬FosB increases immature dendritic spines on CA1 pyramidal cells, whereas ⌬JunD reduced the number of immature and mature spine types, indicating that ⌬FosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ⌬FosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.

Chronic social defeat stress (CSDS) is a well-established rodent model of depression that induces persistent social avoidance. CSDS triggers molecular adaptations throughout the mesocorticolimbic reward circuit, including changes in the activity of dopamine neurons in the ventral tegmental area (VTA), that may also influence drug reward. One limitation of traditional, physical CSDS (PS) is that injury complicates the study of opiate drugs like morphine. Thus, we sought to characterize a variation of CSDS, termed emotional CSDS (ES), that eliminates this confound. We assessed the effect of PS and ES on mesocorticolimbic circuit activation, VTA gene expression, and morphine intake. We found that PS and ES similarly induced ΔFosB in the hippocampus, but only PS significantly increased ΔFosB expression in the prefrontal cortex and striatum. In contrast, cFos expression was similarly reduced by both PS and ES. Interestingly, we found that PS and ES similarly increased voluntary morphine consumption immediately following stress, despite differences in the magnitude of the depressive phenotype and striatal ΔFosB expression at this time point. Combined, these data suggest that both stress paradigms may be useful for investigation of stress-induced changes in drug behavior.

While the etiology of depression is not fully understood, increasing evidence from animal models suggests a role for the ventral tegmental area (VTA) in pathogenesis. In this paper, we investigate the potential role of VTA mechanistic target of rapamycin 2 (TORC2) signaling in mediating susceptibility to chronic social defeat stress (CSDS), a well-established mouse model of depression. Utilizing genetic and viral knockout of Rictor (rapamycin-insensitive companion of target of rapamycin), a requisite component of TORC2, we demonstrate that decreasing Rictor-dependent TORC2 signaling in catecholaminergic neurons, or within the VTA specifically, does not alter susceptibility to CSDS. Opiate abuse and mood disorders are often comorbid, and previous data demonstrate a role for VTA TORC2 in mediating opiate reward. Thus, we also investigated its potential role in mediating changes in opiate reward following CSDS. Catecholaminergic deletion of Rictor increases water, sucrose, and morphine intake but not preference in a two-bottle choice assay in stress-naïve mice, and these effects are maintained after stress. VTA-specific knockout of Rictor increases water and sucrose intake after physical CSDS, but does not alter consummatory behavior in the absence of stress. These findings suggest a novel role for TORC2 in mediating stress-induced changes in consummatory behaviors that may contribute to some aspects of mood disorders.

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