Reinforcing Nicotine Doses Activate Supramammillary VGluT2 Neurons in Mice

Authors

Arima, Y., Min, X., Getachew, B., Nicolas, L., Gillespie, A., Armenta Vega, A., Johnson, S. T., Bi, G., Ye, Z., Ikemoto, S.

Abstract

Background: Although nicotine reinforcement is often attributed to mesolimbic dopamine neurons in the ventral tegmental area, accumulating evidence indicates that additional brain circuits contribute to its reinforcing effects. Aims: The hypothalamic supramammillary region (SuM) has been implicated as one such substrate, yet the cellular targets and circuit mechanisms through which nicotine engages this region remain poorly understood. Methods: We combined RNAscope in situ hybridization to identify nicotinic acetylcholine receptor (nAChR) subunits, intravenous nicotine self-administration in mice to determine doses that reliably support reinforcement, and fiber photometry to monitor calcium activity in SuM VGluT2 neurons in vivo. Results: Mice exhibited reliable nicotine self-administration across a range of doses under fixed-ratio and progressive-ratio schedules. RNAscope analysis revealed prominent expression of the {beta}2 nAChR subunit in VGluT2-expressing neurons projecting from the SuM to the medial septum. Fiber photometry recordings showed that reinforcing doses of nicotine produced rapid, infusion-locked increases in GCaMP signals in SuM VGluT2 neurons. Conclusions: These findings identify nAChR-expressing SuM neurons as a candidate circuit substrate engaged by reinforcing doses of nicotine and extend current models of nicotine reinforcement beyond canonical mesolimbic dopamine pathways.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 19 Aug 2026.

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