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 5

mNAcSh D2 inputs disinhibit VP glutamatergic neurons via inhibition of SST neurons.

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mNAcSh D2 inputs disinhibit VP glutamatergic neurons via inhibition of S...
(A) Schematic showing HSV-based anterograde tracing. (B) Representative images show tdTomato expression in mNAcSh D2 neurons (green). Scale bars: 100 μm (left), 20 μm (right). (C) Sample images reveal postsynaptic VP cells. Scale bars: 100 μm (left), 25 μm (right). (D, F, and H) Schematics of recordings in VP ChAT-mCherry–positive (D), PV-mCherry–positive (F), and SST-mCherry–positive (H) neurons. (E, G, and I) Sample traces (left) and bar plots (right) showing the effects of photoactivating mNAcSh D2 inputs on firing rates of VP ChAT+ neurons (E) [n = 10 neurons; 10 Hz: F(1.704, 15.34) = 0.3289; 20 Hz: F(1.509, 13.58) = 0.006729], PV+ neurons (G) [n = 10 neurons; 10 Hz: F(1.541, 13.87) = 0.07384; 20 Hz: F(1.569, 14.12) = 1.297], and SST+ neurons (I) [n = 10 neurons; 10 Hz: F(1.797, 16.17) = 29.65; 20 Hz: F(1.696, 15.27) = 21.93]. (J) Schematics showing recording of mCherry-positive VP glutamatergic neurons. Green triangle indicates inhibitory VP neurons, presumably receiving input from mNAcSh and innervating VP glutamatergic neurons. (K) Sample traces (left) and bar plots (right) showing firing rates of VP glutamatergic neurons (n = 10 neurons); 10 Hz: F(1.397, 12.57) = 25.53; 20 Hz: F(1.270, 11.43) = 24.80. (L) Schematics of recordings in VP glutamatergic neurons during photoactivating D2 terminals with ablation of SST+ neurons. (M) The effects of ablating VP SST+ neurons on the firing rates of VP glutamatergic neurons (n = 10 neurons); 10 Hz: F (1.336, 12.02) = 0.3194; 20 Hz: F (1.533, 13.79) = 0.6932. (N) Putative VP microcircuits. Increased inhibitory inputs onto VP SST neurons cause a disinhibition of VP glutamatergic neurons, thereby enhancing depression-like behavior. **P < 0.01 and ***P < 0.001 by 1-way repeated-measure ANOVA with Bonferroni’s multiple-comparison test (E, G, I, K, and M). Data are represented as mean ± SEM.