Elevated prelimbic cortex-to-basolateral amygdala circuit activity mediates comorbid anxiety-like behaviors associated with chronic pain
Feng Gao, … , Bing-Jie Hu, Xiang-Dong Sun
Feng Gao, … , Bing-Jie Hu, Xiang-Dong Sun
Published March 14, 2023
Citation Information: J Clin Invest. 2023;133(9):e166356. https://doi.org/10.1172/JCI166356.
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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 7

Blockade of postsynaptic GluA1 insertion into PrLBLA neurons alleviates chronic pain-related anxiety.

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Blockade of postsynaptic GluA1 insertion into PrLBLA neurons alleviates ...
(A) Time scheme for experiments. WB, western blotting; ephys, electrophysiological recording. (B) Schematic of viral injections. (C) Representative image. Scale bar: 50 μm. (D) Representative Western blots. β-actin served as a loading control. (E) Quantitative data in D. n = 3 mice per group. (F) Schematic of electrophysiological recordings of PrLBLA neurons. (G) Representative sEPSC traces. Scale bars: 2 s and 10 pA. (H) Unchanged sEPSC frequency by overexpression of GluA1-ct. n = 12 neurons from 3 mice per group. (I) Reversed sEPSC amplitude in PrLBLA neurons by overexpression of GluA1-ct. n = 12 neurons from 3 mice per group. (J) Representative traces of mouse travel in OFT. (K) Reversed time in center in SNI mice overexpressing GluA1-ct in PrLBLA neurons. n = 8 mice per group. (L) Representative traces of mice travel in EPM. (M) Reversed time in open arms in SNI mice overexpressing GluA1-ct in PrLBLA neurons. n = 8 mice per group. Data shown as mean ± SEM. **P < 0.01; ***P < 0.001. 1-way ANOVA followed by posthoc Tukey’s test (E and M); Kruskal-Wallis test followed by posthoc Dunn’s test (H, I, and K).