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

Maladaptive
consummatory behaviors, including those underlying obesity and disordered
eating, can arise from dysregulated neural circuits
governing motivation and feeding. The extended amygdala is a key integrator of
motivational state and consummatory drive, yet the neuromodulatory mechanisms
that shape its output remain poorly defined. Neurotensin
(NTS) is a neuropeptide expressed throughout the central, peripheral, and
enteric nervous systems with well-established roles in energy balance and
feeding behavior. SBI-553 is a β-arrestin-biased allosteric modulator of NTSR1
that promotes β-arrestin signaling while attenuating Gq-mediated
signaling. Here, we used SBI-553 to examine NTS modulation of GABAergic
signaling within extended amygdala subregions to probe its effects on palatable
food consumption in male and female mice. Using ex vivo
electrophysiology, we found that NTS and SBI-553 differentially modulate spontaneous
GABAergic neurotransmission across extended amygdala subregions. In vivo,
systemic SBI-553 reduces palatable food consumption in both fed and food-deprived mice,
with a greater reduction under fasted conditions. SBI-553 alters neuronal
activation across CeA subregions in a sex- and feeding-state-dependent manner: SBI-553
increases cFos immunofluorescence in the CeAL and CeAC,
while the CeAM remains largely unaffected. These findings
demonstrate that biased NTSR1 modulation engages specific extended amygdala
subcircuits and reduces palatable food consumption across motivational states.
This work supports neurotensinergic modulation as a compelling target for
further investigation into the neural substrates of consummatory behaviors.

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