, Volume 236, Issue 7, pp 1999–2014 | Cite as

Environmental enrichment improves pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain: role of NPAS4

  • Xing-ming Wang
  • Guang-fen Zhang
  • Min Jia
  • Ze-min Xie
  • Jian-jun Yang
  • Jin-chun ShenEmail author
  • Zhi-qiang ZhouEmail author
Original Investigation


Patients suffering from neuropathic pain have a higher incidence of depression and cognitive decline. Although environment enrichment (EE) may be effective in the treatment of neuropathic pain, the precise mechanisms underlying its actions remain determined. The aim of the study was to examine the molecular mechanisms underlying the EE’s beneficial effects in mice with neuropathic pain. EE attenuated the pain threshold reduction, depression-like phenotype, and memory deficit in mice after chronic constriction injury (CCI). Furthermore, EE attenuated decreased neurogenesis and increased inflammation in the hippocampus of mice with neuropathic pain after CCI. Moreover, the suppression of adult hippocampal neurogenesis by temozolomide antagonized the beneficial effects of EE on depression-like phenotype and cognitive deficit in the mice with neuropathic pain. In addition, lipopolysaccharide-induced increase in tumor necrosis factor-α (TNF-α) in the hippocampus antagonized the beneficial effects of EE for these behavioral abnormalities in mice with neuropathic pain. Knock-down of NPAS4 (neuronal PAS domain protein 4) in the hippocampus by lentivirus targeting NPAS4 blocked these beneficial effects of EE in the mice with neuropathic pain. These all findings suggest that hippocampal NPAS4 plays a key role in the beneficial effects of EE on the pain sensitivity, depression-like phenotype, and memory deficit in mice with neuropathic pain. Therefore, it is likely that NPAS4 would be a new therapeutic target for perceptional, affective, and cognitive dimensions in patients with chronic pain.


Neuropathic Neurogenesis Inflammation Depression Cognition Npas4 


Funding information

This study was supported by a grant from the National Natural Science Foundation of China (to Z.Q.Z., no. 81571083, and J.J.Y., no. 81471105).

Compliance with ethical standards

This study was approved by the Ethics Committee of Zhongda Hospital, Nanjing, China, and performed in accordance with the Guide for the Care and Use of Laboratory.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

213_2019_5187_Fig9_ESM.png (814 kb)
Supplemental Figure 1

Cages for animal housing. Mice were housed in the environmental enrichment (EE) cage (60× 40 × 20 cm) and standard enrichment (SE) cage (30× 20 × 10 cm) mice lived. (PNG 813 kb)

213_2019_5187_MOESM1_ESM.tif (4.2 mb)
High Resolution Image (TIF 4321 kb)
213_2019_5187_Fig10_ESM.png (3 mb)
Supplemental Figure 2

Treatment of TMZ decreased hippocampal neurogenesis in adult mice. A, B: Number of BrdU and Ki67 positive cells in the TMZ treated group was significantly decreased compared with control group. The values are the mean ± S.E.M. *P < 0.05, compared with the control group. The detailed statistical analyses are in the supplemental Table 1. Scale bar: 100 μm. (PNG 3064 kb)

213_2019_5187_MOESM2_ESM.tif (12.7 mb)
High Resolution Image (TIF 12992 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Xing-ming Wang
    • 1
  • Guang-fen Zhang
    • 1
  • Min Jia
    • 2
  • Ze-min Xie
    • 2
  • Jian-jun Yang
    • 3
  • Jin-chun Shen
    • 2
    Email author
  • Zhi-qiang Zhou
    • 2
    Email author
  1. 1.Department of Anesthesiology, Zhongda Hospital, Medical SchoolSoutheast UniversityNanjingChina
  2. 2.Department of Anesthesiology, Jinling Hospital, School of MedicineNanjing UniversityNanjingChina
  3. 3.Department of AnesthesiologyThe first affiliated hospital of Zhengzhou UniversityZhengzhouChina

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