The entopeduncular nucleus drives lateral habenula responses to negative but not positive or neutral affective stimuli

Abstract Lateral habenula (LHb) neurons are activated by negative motivational stimuli and play key roles in the pathophysiology of depression. Early reports indicated the possibility that rostral entopeduncular nucleus (rEPN) neurons drive these LHb responses, but this influence remains untested. We find that both rEPN and LHb neurons in rats exhibit similar activation/inhibition patterns after negative/positive motivational stimuli, but that the rEPN influence on LHb firing is surprisingly selective. Temporary rEPN inactivation decreases LHb basal and burst firing, and eliminates LHb responses to footshock-predictive cues occurring 40-100ms but not 10-30ms post-stimulus, nor on responses to positive/neutral motivational stimuli. Additionally, rEPN inactivation partially but not fully reduces LHb responses to signaled footshocks, while excitotoxic rEPN lesions only partially diminish footshock-induced cFos in the LHb and its rostromedial tegmental nucleus targets. Together, our findings indicate an important but selective role of the rEPN in driving LHb responses to motivational stimuli.