Supramammillary neurons projecting to the septum regulate dopamine and motivation for environmental interaction

The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. However, recent studies reported that the stimulation of SuM neurons with neuroactive chemicals, including substances of abuse, is reinforcing. We conducted experiments to illuminate how SuM neurons mediate such effects. The excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by the projections to septal GLU neurons. SuM neurons were active during exploration and approach behavior and diminished activity during sucrose consumption. Consistently, inhibition of SuM neurons disrupted approach responses, but not sucrose consumption. Such functions are similar to those of mesolimbic dopamine neurons. Indeed, the stimulation of SuM-to-septum GLU neurons and septum-to-ventral tegmental area (VTA) GLU neurons activated mesolimbic dopamine neurons. We propose that the supramammillo-septo-VTA pathway is important in reinforcement and approach motivation and may play an important role in mood and substance-use disorders.