Coherent activity at three major lateral hypothalamic neural outputs controls the onset of motivated behavior responses

The lateral hypothalamus (LH) plays an important role in motivated behavior. However, it is not known how LH neural outputs dynamically signal to major downstream targets to organize behavior. We used multi-fiber photometry to show that three major LH neural outputs projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and lateral habenula (LHb) exhibit significant coherent activity in mice engaging motivated responses, which decrease during immobility. Mice engaging active coping responses exhibit increased activity at LH axon terminals that precedes an increase in the activity of serotonin neurons and dopamine neurons, indicating that they may play a role in initiating active responses stemming from LH signal transmissions. The optogenetic activation of LH axon terminals in either the DRN, VTA, or LHb was sufficient to increase mobility but had different effects on passive avoidance and sucrose consumption, suggesting that LH outputs use complementary mechanisms to control behavioral responses. Our results support the notion that the three LH neural outputs play complementary roles in initiating motivated behaviors.