nNOS-expressing neurons in the vmPFC transform pPVT-derived chronic pain signals into anxiety behaviors

• Published in: Nature communications Vol. 11; no. 1; pp. 2501 - 18
• Main Authors: Liang, Hai-Ying, Chen, Zhi-Jin, Xiao, Hui, Lin, Yu-Hui, Hu, Ying-Yi, Chang, Lei, Wu, Hai-Yin, Wang, Peng, Lu, Wei, Zhu, Dong-Ya, Luo, Chun-Xia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.05.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 13/89; 14/19; 14/32; 631/378; 64/110; 64/60; 692/699; 9/74; Activation; Animal models; Animals; Anxiety; Behavior, Animal; Chronic pain; Chronic Pain - enzymology; Chronic Pain - genetics; Chronic Pain - psychology; Humanities and Social Sciences; Humans; Male; Mice; Mice, Inbred C57BL; Midline Thalamic Nuclei - cytology; Midline Thalamic Nuclei - enzymology; Molecular modelling; multidisciplinary; Neurons; Neurons - cytology; Neurons - enzymology; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type I - genetics; Nitric Oxide Synthase Type I - metabolism; Pain; Prefrontal cortex; Prefrontal Cortex - cytology; Prefrontal Cortex - enzymology; Pyramidal cells; Science; Science (multidisciplinary); Thalamus; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16198-5

Anxiety is common in patients suffering from chronic pain. Here, we report anxiety-like behaviors in mouse models of chronic pain and reveal that nNOS-expressing neurons in ventromedial prefrontal cortex (vmPFC) are essential for pain-induced anxiety but not algesia, using optogenetic and chemogenetic strategies. Additionally, we determined that excitatory projections from the posterior subregion of paraventricular thalamic nucleus (pPVT) provide a neuronal input that drives the activation of vmPFC nNOS-expressing neurons in our chronic pain models. Our results suggest that the pain signal becomes an anxiety signal after activation of vmPFC nNOS-expressing neurons, which causes subsequent release of nitric oxide (NO). Finally, we show that the downstream molecular mechanisms of NO likely involve enhanced glutamate transmission in vmPFC CaMKIIα-expressing neurons through S-nitrosylation-induced AMPAR trafficking. Overall, our data suggest that pPVT excitatory neurons drive chronic pain-induced anxiety through activation of vmPFC nNOS-expressing neurons, resulting in NO-mediated AMPAR trafficking in vmPFC pyramidal neurons. Chronic pain usually induces anxiety. Here, the authors report that vmPFC nNOS-expressing neurons are activated by excitatory inputs from pPVT during chronic pain and subsequently induce anxiety-like behaviors in mice through promoting AMPAR trafficking.