Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

Sizer, S. E.; Brown, A. R.; Anderson, J. K.; Summerlin, A. E.; Girgis, I.; Olson, S.; Slosky, L. M.; Leinninger, G. M.; McElligott, Z. A.

doi:10.64898/2026.04.30.722083

bioRxiv · 10.64898/2026.04.30.722083

Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice

Sizer, S. E.·Brown, A. R.·Anderson, J. K.·Summerlin, A. E.·Girgis, I.·Olson, S.·Slosky, L. M.·Leinninger, G. M.·McElligott, Z. A.

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Abstract

Maladaptive consummatory behaviors can arise from dysregulated circuits, like those in the extended amygdala, governing motivation and feeding behaviors. Neurotensin (NTS), expressed throughout the central, peripheral, and enteric nervous systems, has well-established roles in energy balance and feeding. SBI-553, a biased allosteric modulator of NTSR1, recruits {beta}-arrestin while attenuating Gq-mediated signaling. We used SBI-553 to examine NTS modulation GABAergic signaling in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) and probed its effects on food consumption in mice. We found that NTS and SBI-553 differentially modulate GABAergic neurotransmission across extended amygdala subregions. In vivo, SBI-553 reduces palatable food consumption in both fed and food-deprived mice, with greater reductions under fasted conditions, altering activation across CeA subregions in a sex- and feeding-state-dependent manner. In the BNST, differences in SBI-553 altered cFos activity were observed between feeding states. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/722083v3_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1825c16org.highwire.dtl.DTLVardef@16be6acorg.highwire.dtl.DTLVardef@f5561eorg.highwire.dtl.DTLVardef@e8f82c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINTS enhances GABAergic transmission in the CeAL and the ovBNST C_LIO_LISBI-553 blocks NTS-induced increases in sIPSC frequency in the CeAL but not in the ovBNST C_LIO_LISBI-553 attenuates the feeding of a palatable high-carbohydrate food C_LIO_LIThe effect of SBI-553 on feeding is driven by energy deficit/motivation to feed C_LI

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Sizer, S. E., Brown, A. R., Anderson, J. K., Summerlin, A. E., Girgis, I., Olson, S., Slosky, L. M., Leinninger, G. M., McElligott, Z. A.. 2026-05-05. Biased signaling at NTSR1 differentially regulates inhibitory synaptic transmission in the extended amygdala and suppresses motivated feeding in mice. https://doi.org/10.64898/2026.04.30.722083

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