Distinct nucleus accumbens neural pathways underlie separate behavioral features of chronic pain and comorbid depression
Di Liu, Fang-Xia Xu, Zhuang Yu, Xiao-Jing Huang, Ya-Bing Zhu, Li-Juan Wang, Chen-Wei Wu, Xu Zhang, Jun-Li Cao, Jinbao Li
Di Liu, Fang-Xia Xu, Zhuang Yu, Xiao-Jing Huang, Ya-Bing Zhu, Li-Juan Wang, Chen-Wei Wu, Xu Zhang, Jun-Li Cao, Jinbao Li
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Research Article Neuroscience

Distinct nucleus accumbens neural pathways underlie separate behavioral features of chronic pain and comorbid depression

Abstract

The comorbidity of depressive symptoms in chronic pain has been recognized as a key health issue. However, whether discrete circuits underlie behavioral subsets of chronic pain and comorbid depression has not been addressed. Here, we report that dopamine 2 (D2) receptor–expressing medium spiny neurons in the nucleus accumbens medial shell (mNAcSh) mediate pain hypersensitivity and depression-like behaviors in mice after nerve injury. Two separate neural pathways mediate different symptoms. The glutamatergic inputs from the anteromedial thalamic nucleus to mNAcSh D2 neurons that innervated orexin-expressing neurons in the lateral hypothalamic area contributed to pain regulation. In contrast, the lateral septum GABAergic inputs to mNAcSh D2 neurons that disinhibit the ventral pallidum glutamatergic neurons mediated depression-like behaviors. These findings indicate the functional significance of heterogeneous mNAcSh D2 neurons and their neural pathways, providing a perspective for symptom-specific treatments of chronic pain and comorbid depression.

Authors

Di Liu, Fang-Xia Xu, Zhuang Yu, Xiao-Jing Huang, Ya-Bing Zhu, Li-Juan Wang, Chen-Wei Wu, Xu Zhang, Jun-Li Cao, Jinbao Li

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Figure 4

The mNAcShD2-LHAorexin pathway mediates nerve injury–induced pain hypersensitivity.

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The mNAcShD2-LHAorexin pathway mediates nerve injury–induced pain hypers...
(A) Illustration showing virus injection. (B) Representative images show tdTomato expression in mNAcSh D2 cells (green). Scale bars: 100 μm (left), 20 μm (right). (C) Representative images and plot reveal LHA cells (red) labeled with anti-orexin (green). Scale bars: 200 μm (left) and 30 μm (right). (D) Representative traces and input-output function of postsynaptic LHA neurons in mice (n = 12 and 14 cells); F(15, 360) = 5.176. (E) Scheme for virus injection. (F) Representative images and plot reveal mCherry-positive LHA neurons labeled with anti-orexin (green). Scale bar: 30 μm. (G) Light-evoked IPSC was blocked by bicuculline (n = 9 neurons). Paired t test, t8 = 5.119, ***P = 0.0009. (H) Optical IPSC was blocked by TTX and recovered by TTX/4-AP (n = 5 neurons); F(1.057, 4.229) = 16.25. (I) Scheme and representative image showing infection of LHA neurons with hM3Dq-mCherry. Scale bar: 100 μm. (J and K) Mechanical (J) and thermal (K) pain thresholds in SNI mice (n = 6–8 mice/group); t12 = 3.135 (J); t12 = 2.989 (K). (L–N) Sucrose preference (L) and immobility time in TST (M) and FST (N) (n = 6–8 mice/group); t12 = 0.5172 (L); t12 = 0.2910 (M); t12 = 0.4693 (N). (O) Scheme and representative image showing specific infection of LHA neurons with hM4Di-mCherry. Scale bar: 100 μm. (P and Q) Mechanical (P) and thermal (Q) pain thresholds in sham-operated mice (n = 6–8 mice); t12 = 2.987 (P); t12 = 3.791 (Q). (R–T) Sucrose preference (R) and immobility time in TST (S) and FST (T) (n = 6–8 mice); t12 = 0.3659 (R); t12 = 0.9411 (S); t12 = 1.081 (T). *P < 0.05 and **P < 0.01 by 1-way (H) or 2-way (D) repeated-measure ANOVA with Bonferroni’s multiple-comparison test or by 2-tailed t test (J–N and P–T). Data are represented as mean ± SEM.