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Direct paraventricular thalamus-basolateral amygdala circuit modulates neuropathic pain and emotional anxiety

Neuropsychopharmacology volume 49, pages 455–466 (2024)Cite this article

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Abstract

The comorbidity of chronic pain and mental dysfunctions such as anxiety disorders has long been recognized, but the underlying mechanisms remained poorly understood. Here, using a mouse model of neuropathic pain, we demonstrated that the thalamic paraventricular nucleus (PVT) played a critical role in chronic pain-induced anxiety-like behavioral abnormalities. Fiber photometry and electrophysiology demonstrated that chronic pain increased the activities in PVT glutamatergic neurons. Chemogenetic manipulation revealed that suppression of PVT glutamatergic neurons relieved pain-like behavior and anxiety-like behaviors. Conversely, selective activation of PVT glutamatergic neurons showed algesic and anxiogenic effects. Furthermore, the elevated excitability of PVT glutamatergic neurons resulted in increased excitatory inputs to the basolateral complex (BLA) neurons. Optogenetic manipulation of the PVT-BLA pathway bilaterally modulates both the pain-like behavior and anxiety-like phenotypes. These findings shed light on how the PVT-BLA pathway contributed to the processing of pain-like behavior and maladaptive anxiety, and targeting this pathway might be a straightforward therapeutic strategy to both alleviate nociceptive hypersensitivity and rescue anxiety behaviors in chronic pain conditions.

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Fig. 1: Increased activity of PVT glutamatergic neurons in neuropathic pain mice comorbid with anxiety-like phenotypes.
Fig. 2: Inhibition of PVT glutamatergic neurons ameliorated nociceptive hypersensitivity and anxiety-like behaviors in nerve-injured mice.
Fig. 3: Chemogenetic activation of glutamatergic neurons in the PVT enhanced pain response and anxiety-related behaviors.
Fig. 4: Optogenetic manipulation of PVT-BLA projection bilaterally modulated nociceptive hypersensitivity and anxiety-like phenotypes.
Fig. 5: Inhibition of postsynaptic BLA neurons of the PVT attenuated nociceptive hypersensitivity and anxiety-like phenotypes in CCI mice.
Fig. 6: Blockage of glutamatergic receptors in the BLA reversed nociceptive hypersensitivity and anxiety-like behaviors induced by chemogenetic activation of PVT-BLA projection.

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Funding

This work was supported by the following grants: the Clinical Science and Technology Innovation Program from Shanghai Shen Kang Hospital Development Center SHDC12016225 (to ZX), the National Natural Science Foundation of China 82001174 (to DL), and Shanghai Sailing Program 20YF1439100 (to DL).

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  1. These authors contributed equally: Qian-Qian Tang, Yuanyuan Wu.

Authors and Affiliations

  1. Department of Anesthesiology, the International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, 910 Hengshan Road, Shanghai, China

    Qian-Qian Tang, Yuanyuan Wu, Qiang Tao, Yanan Shen, Xiaohu An & Zifeng Xu

  2. Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Di Liu

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Contributions

QQT, DL, and ZX designed the study; QQT, YW, QT, YS, and DL collected the data; QQT, YW, QT, and XA analyzed the data, DL and ZX revised paper critically for important intellectual content.

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Correspondence to Di Liu or Zifeng Xu.

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Tang, QQ., Wu, Y., Tao, Q. et al. Direct paraventricular thalamus-basolateral amygdala circuit modulates neuropathic pain and emotional anxiety. Neuropsychopharmacol. 49, 455–466 (2024). https://doi.org/10.1038/s41386-023-01748-4

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