Supramammillary projections to the lateral preoptic area drive dopamine release and active behavior

The supramammillary nucleus (SuM) is known to promote active, approach-oriented behaviors by engaging ventral tegmental area (VTA) dopamine neurons projecting to the nucleus accumbens (NAc), primarily via a glutamatergic SuM[->]medial septum (MS) pathway. However, the role of other SuM projections in this process remains unclear. Here we combined anatomical tracing, fiber photometry, chemogenetic, and optogenetic approaches to investigate the SuM[->]lateral preoptic area (LPO) pathway. We found that SuM[->]LPO neurons possess extensive collateral projections and are inhibited during consummatory behavior but activated by aversive and unexpected stimuli. Chemogenetic activation of these neurons reduced water intake and immobility during stress, while inhibition enhanced the appetitive phase for ingestive behavior and fear-related immobility. Optogenetic stimulation of SuM[->]LPO terminals reinforced behavior and elicited dopamine release in the NAc. These findings identify the SuM[->]LPO pathway as a distinct circuit that, alongside the SuM[->]MS pathway, engages mesolimbic dopamine signaling to facilitate active behavioral responses to environmental challenges.