Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-03, Vol.110 (5), p.857-873.e9
• Main Authors: Liu, Shijia, Ye, Mao, Pao, Gerald M., Song, Samuel M., Jhang, Jinho, Jiang, Haibei, Kim, Jong-Hyun, Kang, Sukjae J., Kim, Dong-Il, Han, Sung
• Format: Article
• Language: English
• Subjects: Animals; anxiety; Brain Stem; brainstem; breathing; central amygdala; Central Amygdaloid Nucleus; Emotions; Mice; Neural Pathways - physiology; opioidergic; pain; Pain - metabolism; parabrachial nucleus; Parabrachial Nucleus - metabolism; pre-Bötzinger complex; μ-opioid receptor
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.11.029

Breathing can be heavily influenced by pain or internal emotional states, but the neural circuitry underlying this tight coordination is unknown. Here we report that Oprm1 (μ-opioid receptor)-expressing neurons in the lateral parabrachial nucleus (PBL) are crucial for coordinating breathing with affective pain in mice. Individual PBLOprm1 neuronal activity synchronizes with breathing rhythm and responds to noxious stimuli. Manipulating PBLOprm1 activity directly changes breathing rate, affective pain perception, and anxiety. Furthermore, PBLOprm1 neurons constitute two distinct subpopulations in a “core-shell” configuration that divergently projects to the forebrain and hindbrain. Through non-overlapping projections to the central amygdala and pre-Bötzinger complex, these two subpopulations differentially regulate breathing, affective pain, and negative emotions. Moreover, these subsets form recurrent excitatory networks through reciprocal glutamatergic projections. Together, our data define the divergent parabrachial opioidergic circuits as a common neural substrate that coordinates breathing with various sensations and behaviors such as pain and emotional processing. •PBLOprm1 neurons regulate breathing, affective pain, and anxiety in mice•PBLOprm1 neurons constitute projection-defined core and shell subpopulations•Core and shell PBLOprm1 neurons differentially regulate breathing, pain, and anxiety•Core and shell PBLOprm1 neurons form a local recurrent excitatory network Breathing can be influenced by pain and anxiety, but the neural substrate underlying this connection is unknown. Liu et al. report that neurons in the lateral parabrachial nucleus expressing the μ-opioid receptor coordinate breathing with affective pain and negative emotions through divergent output circuits and local recurrent networks in mice.