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Adv."],"published-print":{"date-parts":[[2026,3,6]]},"abstract":"<jats:p>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\/\u0394FosB 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 FosB\/\u0394FosB in vHPC-NAc neurons impaired cocaine reward expression and forced abstinence\u2013induced 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 \u0394FosB expression. To uncover the mechanism of this change in circuit function, we used circuit-specific translating ribosome affinity purification to assess cocaine-induced, FosB\/\u0394FosB-dependent changes in gene expression in vHPC-NAc. We found that cocaine causes a FosB\/\u0394FosB-dependent increase in the expression of calreticulin, an endoplasmic reticulum\u2013resident calcium-buffering protein. Calreticulin expression mediated vHPC-NAc excitability and was necessary for cocaine reward. These findings uncover a noncanonical mechanism by which cocaine increases calreticulin in vHPC leading to decreased vHPC-NAc excitability and drives cocaine seeking and reward.<\/jats:p>","DOI":"10.1126\/sciadv.adv1236","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T18:58:52Z","timestamp":1772650732000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["Transcriptional regulation of ventral hippocampus-nucleus accumbens circuit excitability drives cocaine seeking"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7879-5996","authenticated-orcid":true,"given":"Andrew L.","family":"Eagle","sequence":"first","affiliation":[{"name":"Department of Physiology, Michigan State University, East Lansing, MI 28824, USA."},{"name":"Department of Neuroscience, The University of Texas at Dallas, Richardson, TX 75080, 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