A molecularly defined basalo-prefrontal-thalamic circuit regulates sensory and affective dimensions of pain.

Both the medial prefrontal cortex (mPFC) and thalamus have been implicated in pain regulation. However, the roles of the mPFC-thalamus connection in pain and how the mPFC modulates nociceptive processing within the brain remain unclear. Here, we show that the mPFC neurons that project to thalamus are marked by Foxp2 expression and deactivated in both acute and chronic pain. Persistent inactivation of the mPFC Foxp2 (+) neurons enhances nociceptive sensitivity, while their activation alleviates multiple aspects of pain. Circuit-specific manipulations revealed that the projections to parataenial nucleus, mediodorsal and ventromedial thalamus differentially modulate sensory and affective pain. Additionally, the mPFC Foxp2 (+) neurons receive cholinergic input from the basal forebrain, particularly the horizonal diagonal band (HDB). Notably, activation of the α4β2-containing nicotinic acetylcholine receptor in mPFC exerts antinociceptive effects in Foxp2 (+) neuron-dependent manner. Together, our study defines an HDB→mPFC (Foxp2) →thalamus circuit essential for sensory and affective pain modulation and underscores the therapeutic potential of targeting mPFC cholinergic signaling in chronic pain management.