Somatosensory cortex and central amygdala regulate neuropathic pain-mediated peripheral immune response via vagal projections to the spleen

• Published in: Nature neuroscience 2024-03, Vol.27 (3), p.471-483
• Main Authors: Zhu, Xia, Huang, Ji-Ye, Dong, Wan-Ying, Tang, Hao-Di, Xu, Si, Wu, Qielan, Zhang, Huimin, Cheng, Ping-Kai, Jin, Yuxin, Zhu, Meng-Yu, Zhao, Wan, Mao, Yu, Wang, Haitao, Zhang, Yan, Wang, Hao, Tao, Wenjuan, Tian, Yanghua, Bai, Li, Zhang, Zhi
• Format: Article
• Language: English
• Subjects: 631/378/371; 631/378/3920; 692/699/375/1692; Amygdala; Animal Genetics and Genomics; Animals; Behavioral Sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Cell culture; Central Amygdaloid Nucleus; Chronic pain; Cortex (somatosensory); GABAergic Neurons - physiology; gamma-Aminobutyric Acid - physiology; Glutamatergic transmission; Immune response; Immune system; Lymphocytes T; Male; Mice; Motor nuclei; Neuralgia; Neurobiology; Neurons; Neurosciences; Nuclei (cytology); Pain; Somatosensory Cortex; Spleen; Vagus Nerve; γ-Aminobutyric acid
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/s41593-023-01561-8

Pain involves neuroimmune crosstalk, but the mechanisms of this remain unclear. Here we showed that the splenic T helper 2 (T H 2) immune cell response is differentially regulated in male mice with acute versus chronic neuropathic pain and that acetylcholinergic neurons in the dorsal motor nucleus of the vagus (ACh DMV ) directly innervate the spleen. Combined in vivo recording and immune cell profiling revealed the following two distinct circuits involved in pain-mediated peripheral T H 2 immune response: glutamatergic neurons in the primary somatosensory cortex (Glu S1HL )→ACh DMV →spleen circuit and GABAergic neurons in the central nucleus of the amygdala (GABA CeA )→ACh DMV →spleen circuit. The acute pain condition elicits increased excitation from Glu S1HL neurons to spleen-projecting ACh DMV neurons and increased the proportion of splenic T H 2 immune cells. The chronic pain condition increased inhibition from GABA CeA neurons to spleen-projecting ACh DMV neurons and decreased splenic T H 2 immune cells. Our study thus demonstrates how the brain encodes pain-state-specific immune responses in the spleen. The primary somatosensory cortex and central nucleus of the amygdala project to the spleen via the dorsal motor nucleus of the vagus nerve and regulate the T helper 2 (T H 2) immune cell response in models of neuropathic pain.