Dataset Information

Electroacupuncture improves repeated social defeat stress-elicited social avoidance and anxiety-like behaviors by reducing Lipocalin-2 in the hippocampus.

ABSTRACT:

Background

Post-traumatic stress disorder (PTSD) is a trauma-related disorder that is associated with pro-inflammatory activation and neurobiological impairments in the brain and leads to a series of affective-like behaviors. Electroacupuncture (EA) has been proposed as a clinically useful therapy for several brain diseases. However, the potential role of EA treatment in PTSD and its molecular and cellular mechanisms has rarely been investigated.

Methods

We used an established preclinical social defeat stress mouse model to study whether EA treatment modulates PTSD-like symptoms and understand its underlying mechanisms. To this end, male C57BL/6 mice were subjected to repeated social defeat stress (RSDS) for 6 consecutive days to induce symptoms of PTSD and treated with EA at Baihui (GV 20) and Dazhui (GV 14) acupoints.

Results

The stimulation of EA, but not needle insertion at Baihui (GV 20) and Dazhui (GV 14) acupoints effectively improved PTSD-like behaviors such as, social avoidance and anxiety-like behaviors. However, EA stimulation at the bilateral Tianzong (SI11) acupoints did not affect the PTSD-like behaviors obtained by RSDS. EA stimulation also markedly inhibited astrocyte activation in both the dorsal and ventral hippocampi of RSDS-treated mice. Using next-generation sequencing analysis, our results showed that EA stimulation attenuated RSDS-enhanced lipocalin 2 expression in the hippocampus. Importantly, using double-staining immunofluorescence, we observed that the increased lipocalin 2 expression in astrocytes by RSDS was also reduced by EA stimulation. In addition, intracerebroventricular injection of mouse recombinant lipocalin 2 protein in the lateral ventricles provoked social avoidance, anxiety-like behaviors, and the activation of astrocytes in the hippocampus. Interestingly, the overexpression of lipocalin 2 in the brain also altered the expression of stress-related genes, including monoamine oxidase A, monoamine oxidase B, mineralocorticoid receptor, and glucocorticoid receptor in the hippocampus.

Conclusions

This study suggests that the treatment of EA at Baihui (GV 20) and Dazhui (GV 14) acupoints improves RSDS-induced social avoidance, anxiety-like behaviors, astrocyte activation, and lipocalin 2 expression. Furthermore, our findings also indicate that lipocalin 2 expression in the brain may be an important biomarker for the development of PTSD-related symptoms.

SUBMITTER: Chen YH

PROVIDER: S-EPMC8474847 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPost-traumatic stress disorder (PTSD) is a devastating psychological disorder. Patients with PTSD canonically demonstrate an increased risk for inflammatory diseases, as well as increased sympathetic tone and norepinephrine (NE) outflow. Yet, the exact etiology and causal nature of these physiologic changes remain unclear. Previously, we demonstrated that exogenous NE alters mitochondrial superoxide in T-lymphocytes to produce a pro-inflammatory T-helper 17 (TH17) phenotype, and observed similar TH17 polarization in a preclinical model of PTSD. Therefore, we hypothesized sympathetic-driven neuroimmune interactions could mediate psychological trauma-induced T-lymphocyte inflammation.MethodsRepeated social defeat stress (RSDS) is a preclinical murine model that recapitulates the behavioral, autonomic, and inflammatory aspects of PTSD. Targeted splenic denervation (Dnx) was performed to deduce the contribution of splenic sympathetic nerves to RSDS-induced inflammation. Eighty-five C57BL/6J mice underwent Dnx or sham-operation, followed by RSDS or control paradigms. Animals were assessed for behavioral, autonomic, inflammatory, and redox profiles.ResultsDnx did not alter the antisocial or anxiety-like behavior induced by RSDS. In circulation, RSDS Dnx animals exhibited diminished levels of T-lymphocyte-specific cytokines (IL-2, IL-17A, and IL-22) compared to intact animals, whereas other non-specific inflammatory cytokines (e.g., IL-6, TNF-α, and IL-10) were unaffected by Dnx. Importantly, Dnx specifically ameliorated the increases in RSDS-induced T-lymphocyte mitochondrial superoxide, TH17 polarization, and pro-inflammatory gene expression with minimal impact to non-T-lymphocyte immune populations.ConclusionsOverall, our data suggest that sympathetic nerves regulate RSDS-induced splenic T-lymphocyte inflammation, but play less of a role in the behavioral and non-T-lymphocyte inflammatory phenotypes induced by this psychological trauma paradigm.