Dopamine receptor 1-expressing cells in the ventral hippocampus encode cocaine-context associations

Dopamine (DA) signaling facilitates emotional valence, reward prediction error, and motivation; thus, dysfunctional dopamine signaling has been tied to several neuropsychiatric disorders, including substance use disorder (SUD). While most research has focused on striatal DA signaling, we and others have established that the ventral hippocampus (vHPC) also exhibits topographical organization of mostly non-overlapping dopaminoceptive neuronal populations: those expressing the DA receptor type 1 (D1) or type 2 (D2). Here, we use fiber photometry, optogenetics, and single nuclei RNA-sequencing (snRNA-seq) to explore how dopaminoceptive cells in the vHPC control cocaine-context memory expression. We reveal that vHPC D1 cells are inhibited by cocaine-conditioned contextual cues and that this inhibition is necessary and sufficient for reward-context associations driving cocaine conditioned place preference (CPP). Meanwhile vHPC D2 cells are not dynamically altered by learning but rather support positive reinforcement. Transcriptional changes induced by cocaine CPP encode these distinct functions, with D1 cells undergoing the greatest gene expression changes tied to synaptic signaling and plasticity. Together, these studies broaden our understanding of the role of DA within the larger mesocorticolimbic system and reveal new neuronal and circuit mechanisms underlying how drugs of abuse promote strong associative learning that could drive compulsive drug seeking characteristic of SUD.