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

Andrew J Kesner,Christian T Potter,Christopher G Cover,Coleman B Calva,Yihong Yang,Satoshi Ikemoto,Sue Junn,Ahmed F Abou-Elnaga,Hanbing Lu,Rick Shin,Reuben F Don,Leslie A Ramsey,Dong V Wang

doi:10.1038/s41467-021-23040-z

Andrew J Kesner, Christian T Potter + Show 11 more

Open Access

https://doi.org/10.1038/s41467-021-23040-z

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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.

Highlights

The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal
We examined whether phasic excitation of SuM neurons is reinforcing using an optogenetic intracranial self-stimulation (ICSS) procedure with channelrhodopsin-2 (ChR2) expressed in SuM neurons of wildtype (WT; C57BL/6 J) mice (Fig. 1a, b and Supplementary Fig. 1)
Because of the emerging functional similarities between SuM GLU neurons and ventral tegmental area (VTA) DA neurons described in experiments above, we examined whether behavioral reinforcement by the stimulation of SuM-to-medial septum (MS) GLU neurons depends on DA transmission

Summary

Introduction

The supramammillary region (SuM) is a posterior hypothalamic structure, known to regulate hippocampal theta oscillations and arousal. Inhibition of SuM neurons disrupted approach responses, but not sucrose consumption Such functions are similar to those of mesolimbic dopamine neurons. The stimulation of SuM neurons increases DA concentrations in the ventral striatum (VStr)[4] These initial findings raise the possibility that in addition to positive reinforcement, SuM neurons may participate in increasing approach behavior, a motivation function that is firmly implicated in DA neuron activity[10,11]. Increases in VStr DA activity invigorate approach behavior triggered by canonical rewards such as food and conditioned stimuli[10], and non-canonical rewards such as unconditioned flashes of light[15] Inactivation of this DA system disrupts approach behavior, including instrumental (conditioned) and exploratory (unconditioned) behavior, and such effects can occur without disrupting food intake[16,17,18,19,20], suggesting that DA is more important during approach than consummatory behavior. We conducted fMRI, fiber photometry, and pharmacological experiments to establish the interactions between the SuM-to-septum-to-VTA GLU pathways and the VTA-to-VStr DA pathway

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