A brainstem-thalamic circuitry for affective-motivational responses to cold pain

The medial thalamus is crucial for the sensory and affective-motivational responses to chronic pain. However, a mechanistic understanding of how the distinct subnuclei of the medial thalamus mediate behavioral responses to pain remains lacking. Taking advantage of intersectional viral genetics, chemogenetics, optogenetics, in-vivo imaging, and ex-vivo physiology, we reveal that the neurons in the parafascicular (PF) nuclei of the medial thalamus receive monosynaptic inputs from the lateral parabrachial nuclei (LPBN) in mice. LPBN is an essential nucleus in the ascending pain pathway, receiving projections from the dorsal horn of the spinal cord. The PF neurons downstream of LPBN (PFpost-LPBN) are nociceptive, sensitized by peripheral neuropathy, acutely aversive, and, when activated, drive both sensory and affective-motivational responses to cold pain. In contrast, the LPBN target neurons in the intralaminar centromedian thalamus (CMpost-LPBN), another nociceptive nucleus of the medial thalamus, are primarily involved in the affective-motivational aspects of pain. Together, we reveal that the LPBN, through two closely related thalamic nuclei, influences behavior in mice with cold hypersensitivity due to peripheral neuropathies.