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 8

LS GABAergic neurons modulate depression-like behaviors by connection with the mNAcShD2-VP pathway.

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LS GABAergic neurons modulate depression-like behaviors by connection wi...
(A) Experimental schematic. (B) Percentage of VGAT1-positive neurons labeled with anti-GABA. Scale bar, 20 μm. (C) Light-evoked currents were blocked by TTX and recovered by TTX+4-AP (n = 5); F(1.695, 6.781) = 10.91. (D) Bicuculline blocked light-evoked currents; t7 = 12.68. (E) Representative traces and comparison of IPSC amplitude (n = 11–14 neurons); t23 = 3.536. (F) Sample traces and statistics of IPSC PPR (n = 10–13 neurons); t21 = 2.312. (G) Experimental schematic. (H) The membrane excitability of LS-mNAcShD2-VP neurons in mice (n = 12–14 neurons); F(15, 360) = 6.809, ***P < 0.001. (I and J) The rheobase (I) and RMP (J) of LS-mNAcShD2-VP neurons (n = 12–14 neurons); t24 = 2.681 (I); t24 = 2.886 (J). (K) Schematic and representative image showing GCaMP6s expression. Scale bar, 100 μm. (L–N) Heat maps, averaged responses, and peak ΔF/F of Ca2+ signals upon to von Frey (L), thermal stimuli (M), or tail suspension (N) (n = 6 animals/group); t10 = 0.02689 (L); t10 = 0.1267 (M); t10 = 4.277 (N). (O) Experimental timeline and scheme. (P) Representative traces of ChR2-expressing neurons with photostimulation. (Q and R) Mechanical (Q) and thermal (R) pain thresholds in mice (n = 6–8 mice/group); F(1, 12) = 0.6986 (Q); F(1, 12) = 1.179 (R). (S–U) Sucrose preference (S), immobility time in TST (T) and FST (U) in mice (n = 6–8 mice/group); F(1, 12) = 6.905 (S); F(1, 12) = 4.847 (T); F(1, 12) = 4.898 (U). *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way (C) or 2-way repeated-measures ANOVA with Bonferroni’s multiple comparisons test (H, Q–U). *P < 0.05, **P < 0.01 by 2-tailed t test (E, F, I, J, L–N). Data are represented as mean ± SEM.