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

Hai-Ying Liang,Lei Chang,Yu-Hui Lin,Dong-Ya Zhu,Peng Wang,Ying-Yi Hu,Hui Xiao,Zhi-Jin Chen,Hai-Yin Wu,Wei Lu,Chun-Xia Luo

doi:10.1038/s41467-020-16198-5

Abstract

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.

Highlights

Anxiety is common in patients suffering from chronic pain
Findings from classic pharmacological studies indicate that stimulation of N-methyl-D-aspartic acid receptor (NMDAR) in PL20 or α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs) in IL21 induces anxiety-like behaviors, whereas the activation of gammaamino butyric acid (GABA)A receptors in the ventromedial prefrontal cortex (vmPFC) produces an anxiolytic-like response[22]
Three days after complete Freund’s adjuvant (CFA) injection, mechanical hyperalgesia (Fig. 1a) was observed, and it was accompanied by decreased distance in the center in the open field (OF) test (Fig. 1b) and reduced time in the open arms in the elevated plus maze (EPM) test (Fig. 1c), indicating that anxiety-like behaviors were induced by chronic pain

Summary

Introduction

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. Studies on excitatory transmission at the synaptic level in the ACC have revealed that two forms of longterm potentiation (LTP), the kainite receptor-dependent pre-LTP and the N-methyl-D-aspartic acid receptor (NMDAR)-dependent post-LTP, contribute to interactions between chronic pain and anxiety[12,13]. Findings from classic pharmacological studies indicate that stimulation of NMDARs in PL20 or α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid receptors (AMPARs) in IL21 induces anxiety-like behaviors, whereas the activation of gammaamino butyric acid (GABA)A receptors in the vmPFC produces an anxiolytic-like response[22]. Few studies have focused on this brain region in investigations into chronic pain-induced anxiety[26], so further research is needed. Increased nNOS enzyme activity and NO production in the vmPFC are associated with the long-lasting anxiogenic-like effect induced by predator exposure[30] and acute restraint stress[31]

Methods

Results

Conclusion