A midbrain circuit for high-fat-food induced conditioned taste aversion

Conditioned taste aversion (CTA) is a survival mechanism that prevents consumption of harmful foods. Yet its neural circuits, especially those for solid food aversion, are poorly understood. Using a male mouse model where high-fat food (HFF) was paired with LiCl injections, we identified the median raphe region (MRR) as essential for CTA. Optogenetic activation of MRR glutamatergic neurons replaced LiCl injections, inducing robust HFF aversion. Calcium signaling in MRR neurons increased upon HFF approach post-CTA. We uncovered a necessary glutamatergic projection from the medial preoptic area (MPOA) to the MRR; stimulating this circuit mimicked LiCl, to elicit HFF aversion. Following CTA, synaptic changes in MRR neurons included an increased mEPSC frequency and an altered paired-pulse ratio in the MPOA^VgluT2-MRR pathway. Finally, MRR projections to the medial septum and lateral habenula differentially encode and retrieve CTA memory. These findings define a circuit for aversion learning, offering insights into maladaptive eating behaviors.