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

Abstract

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 elucidate how SuM neurons mediate such effects. Using optogenetics, we found that the excitation of SuM glutamatergic (GLU) neurons was reinforcing in mice; this effect was relayed by their 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 regulates arousal that reinforces and energizes behavioral interaction with the environment.

Seeking motivation and reward: Roles of dopamine, hippocampus, and supramammillo-septal pathway

“…Such coordinating role of MS is consistent with the aforementioned finding that the administration of AMPA into the MS increases seeking responses reinforced by the presentation of salient visual stimuli in rats ( Kesner et al, 2021 ).…”

“…Summarized below are the findings from our recent study ( Kesner et al, 2021 ) supporting that the SuM n Glu -to-MS n Glu -to-VTA n DA circuit participates in seeking motivation ( Fig. 2B ): Optogenetic photostimulation of SuM n Glu , but not GABA or DA neurons, expressing channelrhodopsin-2 (ChR2), an excitatory opsin, reinforces seeking behavior.…”

“…The stimulation of MS n Glu projecting to the preoptic area, but not to the hippocampus, increases locomotor activity ( Zhang et al, 2018a ). In addition, the MS n Glu -to-VTA n DA circuit likely contributes to locomotor activity as this circuit modulates the activity of VTA n DA -to-VStr ( Kesner et al, 2021 ), a well-established circuit for controlling locomotor activity and motivation ( Ikemoto, 2007 ; Ikemoto and Panksepp, 1999 ; Wise, 2004 ).…”

“…By contrast, increased seeking motivation is accompanied by increased environmental activities, which prolong wakefulness. In addition, SuM n inhibition induced by microinjections of GABA receptor agonists decreases locomotor activity ( Kesner et al, 2021 ; Ma and Leung, 2007 ). Conversely, SuM n activation induced by local injections of the GABA A receptor antagonist picrotoxin robustly increases locomotor activity ( Shin and Ikemoto, 2010 ).…”

“…Because the stimulation of SuM n reinforces seeking behavior, it is of interest to determine whether SuM n display RPEs or similarly encoded responses. We investigated whether SuM n selectively respond to reward classic and CS reward , using electrophysiology recording procedures in freely-moving mice ( Kesner et al, 2021 ). Mice were trained to lever-press for a sucrose reward ( Fig.…”