Multimodal interrogation of ventral pallidum projections reveals projection-specific signatures and opposite roles in cocaine withdrawal

The ventral pallidum (VP) is central to reward seeking and withdrawal from drugs of abuse. A characteristic of the VP is the diversity of its projection targets. Yet, it remains unknown whether different VP projections also differ in other aspects, such as their transcriptome, physiology and relevance to drug reward. In this study we perform a multimodal dissection of four major projections of the VP – to the lateral hypothalamus (VP→LH), ventral tegmental area (VP→VTA), lateral habenula (VP→LHb) and mediodorsal thalamus (VP→MDT) – with physiological, anatomical, genetic and behavioral tools and show significant differences between projections in all aspects. Specifically, the VP→LHand VP→VTAprojections show minimal overlap and stand out as having opposite properties – VP→LHneurons show higher excitability compared to VP→VTAneurons, different pattern of inputs and differentially expressed genes. Moreover, inhibition of VP→LHprojections diminishes, while inhibition of VP→VTAenhances cocaine preference after cocaine withdrawal. This demonstrates that VP projections are heterogenous neuron populations with different roles in cocaine withdrawal.