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<p>Painful diabetic neuropathy (PDN) is frequently accompanied by anxiety, yet the neural circuit mechanisms associated with nociceptive hypersensitivity to affective dysfunction remain unclear. Here we combined brain-wide c-Fos mapping, viral tracing, in vivo fiber photometry, whole-cell recordings, and projection-specific opto/chemogenetics in a mouse model of streptozotocin-induced PDN to define a thalamo–cortex circuit for pain–anxiety comorbidity. Within the posterior insular cortex (pIC), CaMKIIα⁺ excitatory neurons were recruited in PDN mice with comorbid anxiety, exhibiting heightened neuronal excitability and enhanced excitatory synaptic input. Bidirectional chemogenetic modulation of pIC<sup>CaMKIIα</sup> neurons oppositely regulated anxiety-like behavior and mechanical hypersensitivity without locomotor or glycemic confounds. Circuit mapping identified a monosynaptic excitatory projection from the paraventricular thalamus (PVT) to the pIC; PVT<sup>CaMKIIα</sup> neurons were hyperactive in PDN, and projection-defined manipulation of the PVT<sup>CaMKIIα</sup> to pIC<sup>CaMKIIα</sup> pathway bidirectionally controlled the behavioral phenotypes. <i>Cacna1c</i> was upregulated in the PVT of PDN mice; its knockdown in pIC-projecting PVT<sup>CaMKIIα</sup> neurons attenuated both pain and anxiety-like behaviors. Together, these results delineate a thalamo–cortex excitatory pathway that couples nociceptive and affective dimensions of PDN and suggest that selective targeting of the PVT<sup>CaMKIIα</sup> to pIC<sup>CaMKIIα</sup> circuit may provide coordinated relief of pain and anxiety-related symptoms.</p><p></p>

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Excitatory paraventricular thalamus–posterior insular cortex circuit mediates pain–anxiety comorbidity in diabetic neuropathy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月27日

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  • Min Wei,
  • Jiayin Shou,
  • Jing Yang,
  • Siqing Cai,
  • Qiyuan Bai,
  • Jinwen Hou,
  • Ye Jiang,
  • Shixiong Shen,
  • Zhuoying Yu,
  • Xinru Zhao,
  • Yongzheng Han,
  • Jie Cai,
  • Xue-wei Yang,
  • Zhengqian Li,
  • Daqing Ma,
  • Guo-Gang Xing,
  • Min Li

摘要

Painful diabetic neuropathy (PDN) is frequently accompanied by anxiety, yet the neural circuit mechanisms associated with nociceptive hypersensitivity to affective dysfunction remain unclear. Here we combined brain-wide c-Fos mapping, viral tracing, in vivo fiber photometry, whole-cell recordings, and projection-specific opto/chemogenetics in a mouse model of streptozotocin-induced PDN to define a thalamo–cortex circuit for pain–anxiety comorbidity. Within the posterior insular cortex (pIC), CaMKIIα⁺ excitatory neurons were recruited in PDN mice with comorbid anxiety, exhibiting heightened neuronal excitability and enhanced excitatory synaptic input. Bidirectional chemogenetic modulation of pICCaMKIIα neurons oppositely regulated anxiety-like behavior and mechanical hypersensitivity without locomotor or glycemic confounds. Circuit mapping identified a monosynaptic excitatory projection from the paraventricular thalamus (PVT) to the pIC; PVTCaMKIIα neurons were hyperactive in PDN, and projection-defined manipulation of the PVTCaMKIIα to pICCaMKIIα pathway bidirectionally controlled the behavioral phenotypes. Cacna1c was upregulated in the PVT of PDN mice; its knockdown in pIC-projecting PVTCaMKIIα neurons attenuated both pain and anxiety-like behaviors. Together, these results delineate a thalamo–cortex excitatory pathway that couples nociceptive and affective dimensions of PDN and suggest that selective targeting of the PVTCaMKIIα to pICCaMKIIα circuit may provide coordinated relief of pain and anxiety-related symptoms.