Cocaine, via ?FosB, remodels gene expression and excitability in ventral hippocampus
Ventral hippocampus (vHPC) CA1 pyramidal neurons send glutamatergic projections to nucleus accumbens (NAc), and this vHPC-NAc circuit mediates cocaine seeking and reward, but it is unclear whether vHPC-NAc neuron properties are modulated by cocaine exposure to drive subsequent behavior. The immediate early gene transcription factor ?FosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but it's function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of ?FosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence-induced seeking. We also found that vHPC-NAc excitability was decreased by experimenter-administered repeated cocaine and cocaine self-administration, and this cocaine-induced excitability decrease was mediated by ?FosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification (TRAP) to assess cocaine-induced, ?FosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a ?FosB-dependent increase in the expression of calreticulin, an ER-resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a novel, non-canonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drive cocaine seeking and reward. Overall design: TRAP experiment conducted on saline/coc/cocFlox groups