Cell Type-Specific Encoding of Cocaine-Conditioned Responses in the Lateral Preoptic Area

The lateral preoptic area (LPO) is a functionally heterogeneous hypothalamic structure that is increasingly recognised for its role in motivated and drug-seeking behaviours. Although prior studies have shown that LPO neurons exhibit diverse activity patterns during cocaine self-administration, the specific contributions of glutamatergic and GABAergic populations to conditioned responses to cocaine remain unclear. In this study, we recorded the activity of LPO glutamatergic (vglut2-expressing) and GABAergic (vgat-expressing) neuronal subpopulations during cocaine conditioning to identify how these cell types respond to drug-associated cues in awake, behaving mice. Our results revealed that, after cocaine conditioning, both glutamatergic and GABAergic populations showed reduced activity upon entry into the cocaine-paired chamber. However, only glutamatergic neurons exhibited increased activity when mice entered the saline-paired chamber. The magnitude of these activity changes was also correlated with behavioural outcomes: reduced GABAergic activity was associated with greater preference for the cocaine-paired chamber, whereas stronger glutamatergic responses were associated with greater preference for the saline-paired chamber. These findings indicate that LPO GABAergic and glutamatergic neurons exhibit distinct, cell type-specific patterns during cocaine-conditioned place preference. Rather than indicating opposing motivational states, the results highlight that LPO activity relates to conditioned behaviours in a cell type- and context-dependent manner. By linking activity in glutamatergic and GABAergic neurons with conditioned responses, this work provides initial evidence for how LPO circuits may contribute to drug-associated learning.