Iben-Daoudi, H.; Ba-Mhamed, S.; Moubarrad, F.-Z. L.; Bennis, M.; LANDRY, M.; Ouhaz, Z.

The mediodorsal thalamus (MD) modulates pain through thalamocortical regulation of the mPFC. Yet, MD is often treated as a single anatomical and functional entity despite marked internal heterogeneity. Here, we tested whether medial-central MD (MDmc) and lateral MD (MDl) subdivisions exert dissociable control over sensory-discriminative and affective-motivational components of pain by engaging the anterior cingulate cortex (ACC) and prelimbic cortex (PrL). Using subdivision-selective excitotoxic lesions in rats, combined with anterograde tracing, laminar activity mapping, and projection-specific optogenetic manipulation of MDmc and MDl terminals in ACC or PrL, we determined the contribution of each subdivision and the underlying MD-PFC circuit mechanisms. Behaviorally, MDmc and MDl lesions induced mechanical and thermal hypersensitivity, but only MDmc lesions increased pain-related avoidance. Anatomical analyses showed that MDl preferentially innervated ACC PV cells, whereas MDmc more strongly targeted ACC SOM cells. Lesions further produced subdivision-dependent reorganization of nociception-evoked cFos activity in layers 2/3 and 5 and altered PV/SOM interneuron recruitment. Optogenetic manipulations revealed pathway-specific effects: MDmc-ACC/PrL manipulations enhanced nociceptive gain and avoidance, whereas MDl-ACC inhibition increased hypersensitivity while reducing avoidance, and MDl-PrL inhibition increased both nociceptive sensitivity and avoidance. Together, these findings identify MD subdivision-specific thalamocortical pathways that recruit distinct inhibitory microcircuits within ACC and PrL, thereby differentially shaping sensory-discriminative and affective-motivational components of pain.