Elevated prelimbic cortex-to-basolateral amygdala circuit activity mediates comorbid anxiety-like behaviors associated with chronic pain
Feng Gao, Jie Huang, Guo-Bin Huang, Qiang-Long You, Shan Yao, Shen-Ting Zhao, Jian Liu, Cui-Hong Wu, Gui-Fu Chen, Shi-Min Liu, Zongyan Yu, Yan-Ling Zhou, Yu-Ping Ning, Shenquan Liu, Bing-Jie Hu, Xiang-Dong Sun
Feng Gao, Jie Huang, Guo-Bin Huang, Qiang-Long You, Shan Yao, Shen-Ting Zhao, Jian Liu, Cui-Hong Wu, Gui-Fu Chen, Shi-Min Liu, Zongyan Yu, Yan-Ling Zhou, Yu-Ping Ning, Shenquan Liu, Bing-Jie Hu, Xiang-Dong Sun
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Research Article Neuroscience

Elevated prelimbic cortex-to-basolateral amygdala circuit activity mediates comorbid anxiety-like behaviors associated with chronic pain

Abstract

Chronic pain can cause both hyperalgesia and anxiety symptoms. However, how the two components are encoded in the brain remains unclear. The prelimbic cortex (PrL), a critical brain region for both nociceptive and emotional modulations, serves as an ideal medium for comparing how the two components are encoded. We report that PrL neurons projecting to the basolateral amygdala (PrLBLA) and those projecting to the ventrolateral periaqueductal gray (PrLl/vlPAG) were segregated and displayed elevated and reduced neuronal activity, respectively, during pain chronicity. Consistently, optogenetic suppression of the PrL-BLA circuit reversed anxiety-like behaviors, whereas activation of the PrL-l/vlPAG circuit attenuated hyperalgesia in mice with chronic pain. Moreover, mechanistic studies indicated that elevated TNF-α/TNFR1 signaling in the PrL caused increased insertion of GluA1 receptors into PrLBLA neurons and contributed to anxiety-like behaviors in mice with chronic pain. Together, these results provide insights into the circuit and molecular mechanisms in the PrL for controlling pain-related hyperalgesia and anxiety-like behaviors.

Authors

Feng Gao, Jie Huang, Guo-Bin Huang, Qiang-Long You, Shan Yao, Shen-Ting Zhao, Jian Liu, Cui-Hong Wu, Gui-Fu Chen, Shi-Min Liu, Zongyan Yu, Yan-Ling Zhou, Yu-Ping Ning, Shenquan Liu, Bing-Jie Hu, Xiang-Dong Sun

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Figure 10

TNFR1 in PrLBLA neurons is required for dysfunction of excitatory synaptic activity and anxiety-like behaviors in chronic pain.

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TNFR1 in PrLBLA neurons is required for dysfunction of excitatory synapt...
(A) Higher level of Tnfr1 in PrLBLA neurons. n = 14 and 11 tubes for Tnfr2 and Tnfr1. (B) Schematic for viral injections. (C) Representative image; dotted lines denote the boundaries of PrL. Scale bar: 50 μm. (D) Left, representative Western blots. GAPDH served as a loading control. Right, quantified data. n = 4 mice per group. (E) Unaltered pain threshold in Tnfr1-KD mice. n = 9, 9, 8, and 9 mice for Control+sham, Tnfr1-KD+sham, Control+SNI, and Tnfr1-KD+SNI group, respectively. (F and H) Representative traces of mice travel in OFT (F) and in EPM (H). (G) Increased time in center in SNI mice by deletion of Tnfr1 in PrLBLA neurons. n = 8 mice per group. (I) Reversed time in open arms in SNI mice by deletion of Tnfr1 in PrLBLA neurons. n = 8 mice per group. (J) Representative sEPSC traces. Scale bars: 2 s and 10 pA. (K) Not changed sEPSC amplitudes in SNI mice by deletion of Tnfr1 in PrLBLA neurons. n = 18, 16, 16, and 17 neurons from 4 mice for Control+sham, Tnfr1-KD+sham, Control+SNI, and Tnfr1-KD+SNI groups, respectively. (L) Diminished difference in firing frequencies. Left, representative firing traces. Scale bars: 200 ms, 20 mV. Right, quantitative data. n = 15 neurons from 4 mice per group. Data shown as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. Mann Whitney U test (A); Student’s t test (D); Kruskal-Wallis test followed by Dunn’s test (E, G, and K); 1-way ANOVA followed by posthoc Tukey’s test (I); 2-way repeated-measures ANOVA (L).