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

The supramammillary nucleus (SuM) promotes active behavioral responding by engaging ventral tegmental area (VTA) dopamine neurons that project to the nucleus accumbens (NAc), primarily via a glutamatergic SuM→medial septum (MS) pathway. However, the contribution of additional SuM projections to this process remains unclear. Here we combined anatomical tracing, fiber photometry, chemogenetic, and optogenetic approaches to investigate the SuM→lateral preoptic area (LPO) pathway in mice. SuM→LPO neurons possessed extensive collateral projections and were inhibited during consummatory behavior but activated by aversive and unexpected stimuli. Chemogenetic activation of these neurons reduced water intake and immobility during stress, whereas inhibition enhanced the appetitive phase of ingestive behavior and fear-related immobility. Optogenetic stimulation of SuM→LPO terminals was reinforcing, markedly increasing active behavioral responding, and the same stimulation elicited dopamine release in the NAc. These findings suggest the SuM→LPO pathway as a distinct circuit that, alongside the SuM→MS pathway, engages mesolimbic dopamine signaling to promote active behavioral responding to environmental challenges.