LAMINAR PARVALBUMIN AND SOMATOSTATIN ACTIVATION IN ACC TRACKS MEDIODORSAL THALAMUS CONTROL OF PAIN BEHAVIOR

The mediodorsal thalamus (MD) is increasingly recognized as a key thalamo-prefrontal hub for pain; however, how distinct MD subdivisions shape anterior cingulate cortex (ACC) inhibitory microcircuits remains unclear. We combined subdivision-selective NMDA lesions (MDmc vs MDl), anterograde MD-ACC tracing, and quantified ACC axonal density and putative contacts onto parvalbumin (PV) and somatostatin (SOM) interneurons. In addition to a laminar PV/SOM activity mapping (cFos), and projection-specific optogenetic inhibition/activation of MD-ACC terminals during von Frey, hot-plate, and place escape/avoidance testing were performed in male and female rats. Tracing analyses of MD-ACC pathways suggest that MDmc and MDl establish distinct terminal field organizations in the ACC and may differentially interact with PV and SOM-associated inhibitory circuitry. Using subdivision-targeted excitotoxic lesions combined with laminar cFos mapping, we observed consistent lesion-related remodeling of ACC layer-specific activity patterns alongside altered recruitment of inhibitory interneuron populations. Causal tests using optogenetic inhibition and activation of MDmc-ACC and MDl-ACC afferents demonstrate that these pathways bidirectionally modulate nociceptive responsiveness, while showing divergent influences on the affective-emotional component of pain. Overall, our results highlight functional specialization across MD subdivisions in regulating ACC inhibition and the multidimensional expression of pain. In summary, the MD does not operate as a homogeneous pain-control node; its subdivisions differentially engage ACC PV and SOM microcircuits to tune pain dimensions. Given the conserved MD-ACC network in humans and its involvement in chronic pain and affective dysregulation, our findings suggest that subdivision-specific thalamo-cingulate inhibition is a mechanistically grounded target for more precise neuromodulation and pain relief.