Characterization of a Nociceptive Neural Ensemble in the Nucleus Accumbens Shell

The experience of pain encompasses both nociceptive sensory and negative affective dimensions. A key first step to understand the affective dimension is to functionally and genetically identify nociceptive neurons connected across affective-motivational neural circuits in acute and chronic pain states. We recently identified a nociceptive subpopulation of negative valence basolateral amygdala (BLA) neurons essential for pain aversion. Here, we characterize a downstream target of BLA nociceptive neurons—the nucleus accumbens Shell (NAcSh). Broadly, aberrant activity of the NAcSh has been linked to motivational deficits in chronic pain, yet much remains unknown regarding specific NAcSh nociceptive cell-types or their modulation by BLA nociceptive neurons. Here, we used targeted recombination in active populations (TRAP) mice to genetically capture nociceptive NAcSh neurons (nociTRAP) with combined immunohistochemistry, fluorescent in situ hybridization (FISH), and viral tract tracing. We identified a previously unreported posterior medial NAcSh subregion—anatomically encompassed by the Islands of Cajella granule cell clusters—that contains numerous nociTRAP neurons. This region, which we termed the “NAcre” (named after the inner shell layer of mollusks), receives projections from nociceptive BLA neurons. Importantly, the majority of acute nociTRAP NAcre neurons also display increased immediate early gene FOS expression to light touch following a peripheral nerve injury, revealing consistent activation across pain states independent of stimulus sensory modality. Finally, using multiplexed FISH, we found that nociTRAP NAcre neurons, while molecularly heterogeneous, were primarily medium spiny neurons expressing dopamine receptor 2 and kappa opioid receptor mRNA. In total, the NAcre is a highly nociceptive subregion of the posterior medial NAcSh that receives nociceptive transmissions from the BLA and may be involved in pain-related kappa opioid aversion processes. Further work will determine the necessity and sufficiency of this neural population for affective-motivational behaviors in acute and chronic pain states. Grant support from 5R00DA043609-04 - Deconstructing the network mechanisms of chronic pain and reward in the amygdala (Independent Phase).