The supramammillary nucleus (SuM) is a posterior hypothalamic nucleus that provides dense projections to the septo-hippocampal system. Past research on SuM and septal systems has primarily focused on their role in hippocampal theta rhythm activity, as well as in stress and aversion. However, classically, the septum is implicated in reward as it is the first brain nuclei identified as eliciting reward signals when electrically stimulated. Likewise, our lab has shown that pharmacological excitation of SuM neurons induces reward. Given this information, we feel these closely linked brain regions are understudied in terms of their roles in reward processes and affect. We first found that rats self-administered the excitatory glutamate agonist, AMPA, into the septal area. Since the SuM provides dense glutamatergic input to the septal area, we designed experiments to investigate whether the SuM mediates reward via its connection to the septal area. We confirmed general cell body stimulation of SuM is rewarding using a human synapsin-1 mediated channelrhodopsin-2 (ChR2) in wild-type (C57/BL7) mice. Mice with ChR2 and optic fibers in SuM quickly learned to respond on a lever reinforced by photostimulation and switch responding when lever assignments are reversed. Mice do not reliably self-stimulate when optic fibers are placed in areas adjacent to SuM - the mammillary bodies or ventral tegmental area. Next, using a Cre-dependent ChR2 and vGlut2-Cre, vGat-Cre or Th-Cre mice, we show this rewarding excitation of SuM neurons is likely mediated by glutamatergic neurons, but not dopaminergic or GABAergic neurons. Then using optogenetic terminal-stimulation we dissect which glutamatergic projections from SuM mediate self-stimulation behavior. Mice learned to respond for the stimulation of SuM glutamatergic neurons terminating in the lateral septum, but not terminals in the paraventricular thalamic nucleus, ventral subiculum, or basal forebrain. Currently we are conducting complementary experiments to study the effect of inhibition of SuM-septal glutamate neurons on motivational processes. We conclude that stimulation of septal cell bodies, whether via direct administration of AMPA, or optogenetic elicited release of glutamate from supramammillary neurons, is rewarding. This data speaks to current controversy in the field, as the septums involvement in reward related processes has recently been called into question. Our results implicate this highly conserved midline system in modulating positive affective processes, warranting future research into its role in psychiatric disorders such as anxiety and addiction.
