Cocaine, via ΔFosB, remodels gene expression and excitability in ventral hippocampus

Eagle, A. L.; Doyle, M. A.; Sugimoto, C.; Dykstra, M. M.; Kuhn, H. M.; Murray, B. R.; Bastle, R. M.; He, J.; Maze, I.; Mazei-Robison, M.; Robison, A. J.

doi:10.1101/2024.11.06.621895

bioRxiv · 10.1101/2024.11.06.621895

Cocaine, via ΔFosB, remodels gene expression and excitability in ventral hippocampus

Eagle, A. L.·Doyle, M. A.·Sugimoto, C.·Dykstra, M. M.·Kuhn, H. M.·Murray, B. R.·Bastle, R. M.·He, J.·Maze, I.·Mazei-Robison, M.·Robison, A. J.

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Abstract

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 {Delta}FosB is induced throughout the brain by cocaine and is critical for cocaine seeking, but its function in vHPC-NAc neurons is not understood. We now show that circuit-specific knockout of {Delta}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 {Delta}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, {Delta}FosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a {Delta}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 drives cocaine seeking and reward.

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Eagle, A. L., Doyle, M. A., Sugimoto, C., Dykstra, M. M., Kuhn, H. M., Murray, B. R., Bastle, R. M., He, J., Maze, I., Mazei-Robison, M., Robison, A. J.. 2024-11-07. Cocaine, via ΔFosB, remodels gene expression and excitability in ventral hippocampus. https://doi.org/10.1101/2024.11.06.621895

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