The mediodorsal thalamus is a higher order thalamic nucleus critical for many cognitive behaviors. Defined by its reciprocal connections with the prefrontal cortex, the mediodorsal thalamus receives strong projections from chemosensory cortical areas for taste and smell, gustatory cortex and piriform cortex. Recent studies indicate the mediodorsal thalamus is involved in experience-dependent chemosensory processes, including olfactory attention and discrimination and the hedonic perception of odor-taste mixtures. How novel and familiar chemosensory stimuli are represented within this structure remains unclear. Here, we compared the expression of c-Fos in the mediodorsal thalami of rats familiar with an odor, a taste, or an odor-taste mixture with those that sampled the stimuli for the first time. We found that familiar tastes or odor-taste mixtures induced significantly greater c-Fos expression in the mediodorsal thalamus than novel tastes or odor-taste mixtures, whereas novel odors induced greater c-Fos expression than familiar odors. These experience-dependent and modality-specific differences in c-Fos expression may relate to the behavioral relevance of the chemosensory stimulus, including odor neophobia. In a two-bottle brief-access preference task, rats preferred water to isoamyl acetate-odorized water over multiple days. However, after experience with isoamyl acetate mixed with sucrose (odor-taste mixture), the preference for water was eliminated. These findings demonstrate that experience with chemosensory stimuli modulates responses in the mediodorsal thalamus, suggesting this structure plays an integral role in communicating behaviorally relevant chemosensory information to higher order areas to guide food-related behaviors.

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