Abstract
<jats:p>Orexin (hypocretin) neurons (OXN) broadcast arousal related signals across the forebrain, yet how their inputs shape motivated behavior remains poorly understood. The supramammillary region (SuM), a posterior hypothalamic structure implicated in arousal, active coping and reward seeking, receives dense orexin innervation. Here, we define how orexinergic terminals in the SuM (OXNSuM) integrate threat salience with approach motivational processes. Using viral tracing and RNAscope, we show that SuM neurons express both orexin receptor subtypes, with type 2 receptors predominating. Fiber photometry recordings from OXNSuM terminals reveal strong activation by footshock and conditioned threat cues, modest responses to salient sensory stimuli, and pronounced suppression during water consumption. Optogenetic stimulation of OXNSuM terminals reinforces instrumental responding, biases real time place preference, and elicits rapid, stimulation locked dopamine release in the nucleus accumbens. These findings identify an orexin to SuM pathway that is engaged by uncertainty and threat yet promotes approach behavior through coupling to mesolimbic dopamine, revealing a mechanism linking hypothalamic arousal signals to adaptive motivational responses.</jats:p>