Experience-Dependent Induction of Hippocampal ΔFosB Controls Learning

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. Delta 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 Delta 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 Delta FosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence Delta FosB transcriptional activity by expressing Delta JunD (a negative modulator of Delta FosB transcriptional function) or to overexpress Delta FosB, we demonstrate that HPC Delta FosB regulates learning and memory. Specifically, Delta JunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general Delta FosB overexpression also impaired learning. Delta JunD expression in HPC did not affect anxiety or natural reward, but Delta FosB overexpression induced anxiogenic behaviors, suggesting that Delta FosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of Delta FosB increases immature dendritic spines on CA1 pyramidal cells, whereas Delta JunD reduced the number of immature and mature spine types, indicating that Delta FosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that Delta FosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory.