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.

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Social Defeat Stress Decreases mRNA for Monoamine Oxidase A and Increases 5-HT Turnover in the Brain of Male Nile Tilapia (Oreochromis niloticus)

Frontiers in Pharmacology ◽

10.3389/fphar.2018.01549 ◽

2019 ◽

Vol 9 ◽

Cited By ~ 7

Author(s):

Yuki Higuchi ◽

Tomoko Soga ◽

Ishwar S. Parhar

Keyword(s):

Monoamine Oxidase ◽

Oreochromis Niloticus ◽

Nile Tilapia ◽

Social Defeat ◽

Monoamine Oxidase A ◽

Social Defeat Stress ◽

Nile Tilapia Oreochromis Niloticus ◽

The Brain

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Roles of Toll-like receptor 2/4, monoacylglycerol lipase, and cyclooxygenase in social defeat stress-induced prostaglandin E2 synthesis in the brain and their behavioral relevance

Scientific Reports ◽

10.1038/s41598-019-54082-5 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Xiang Nie ◽

Shiho Kitaoka ◽

Masakazu Shinohara ◽

Akira Kakizuka ◽

Shuh Narumiya ◽

...

Keyword(s):

Arachidonic Acid ◽

Social Defeat ◽

Lipid Mediator ◽

Dependent Manner ◽

Monoacylglycerol Lipase ◽

Social Avoidance ◽

Toll Like Receptor ◽

Social Defeat Stress ◽

Free Arachidonic Acid ◽

The Brain

AbstractInflammation in the brain and periphery has been associated with stress-related pathology of mental illness. We have shown that prostaglandin (PG) E2, an arachidonic acid-derived lipid mediator, and innate immune receptors Toll-like receptor (TLR) 2/4 are crucial for repeated stress-induced behavioral changes in rodents. However, how the stress induces PGE2 synthesis in the brain and whether TLR2/4 are involved in the PGE2 synthesis remain unknown. Using mice lacking TLR2 and TLR4 in combination, here we show that social defeat stress (SDS) induced the PGE2 synthesis in subcortical, but not cortical, tissues in a TLR2/4-dependent manner. It is known that PGE2 in the brain is mainly derived by monoacylglycerol lipase (MAGL)-mediated conversion of endocannabinoid 2-arachidonoylglycerol to free-arachidonic acid, a substrate for cyclooxygenase (COX) for PGE2 synthesis. We found that TLR2/4 deletion reduced the mRNA expression of MAGL and COX1 in subcortical tissues after repeated SDS. Perturbation of MAGL and COX1 as well as COX2 abolished SDS-induced PGE2 synthesis in subcortical tissues. Furthermore, systemic administration of JZL184, an MAGL inhibitor, abolished repeated SDS-induced social avoidance. These results suggest that SDS induces PGE2 synthesis in subcortical regions of the brain via the MAGL-COX pathway in a TLR2/4-dependent manner, thereby leading to social avoidance.

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Hop Bitter Acids Increase Hippocampal Dopaminergic Activity in a Mouse Model of Social Defeat Stress

International Journal of Molecular Sciences ◽

10.3390/ijms21249612 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9612

Author(s):

Yasuhisa Ano ◽

Shiho Kitaoka ◽

Rena Ohya ◽

Keiji Kondo ◽

Tomoyuki Furuyashiki

Keyword(s):

Mouse Model ◽

Chronic Administration ◽

Social Defeat ◽

Underlying Mechanism ◽

Mental Illnesses ◽

Social Avoidance ◽

Social Defeat Stress ◽

Dopaminergic Activity ◽

Healthy Older Adults ◽

Bitter Acids

As daily lifestyle is closely associated with mental illnesses, diet-based preventive approaches are receiving attention. Supplementation with hop bitter acids such as iso-α-acids (IAA) and mature hop bitter acids (MHBA) improves mood states in healthy older adults. However, the underlying mechanism remains unknown. Since acute oral consumption with IAA increases dopamine levels in hippocampus and improves memory impairment via vagal nerve activation, here we investigated the effects of chronic administration of hop bitter acids on the dopaminergic activity associated with emotional disturbance in a mouse model of repeated social defeat stress (R-SDS). Chronic administration of IAA and MHBA significantly increased dopaminergic activity based on the dopamine metabolite to dopamine ratio in the hippocampus and medial prefrontal cortex following R-SDS. Hippocampal dopaminergic activity was inversely correlated with the level of R-SDS-induced social avoidance with or without IAA administration. Therefore, chronic treatment with hop bitter acids enhances stress resilience-related hippocampal dopaminergic activity.

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Ingestion of probiotic (Lactobacillus helveticus and Bifidobacterium longum) alters intestinal microbial structure and behavioral expression following social defeat stress

Scientific Reports ◽

10.1038/s41598-021-83284-z ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Katherine A. Partrick ◽

Anna M. Rosenhauer ◽

Jérémie Auger ◽

Amanda R. Arnold ◽

Nicole M. Ronczkowski ◽

...

Keyword(s):

Social Stress ◽

Bifidobacterium Longum ◽

Social Defeat ◽

Lactobacillus Helveticus ◽

Rrna Gene ◽

Social Avoidance ◽

Social Defeat Stress ◽

Microbial Structure ◽

Microbial Composition ◽

Anti Inflammatory

AbstractSocial stress exacerbates anxious and depressive behaviors in humans. Similarly, anxiety- and depressive-like behaviors are triggered by social stress in a variety of non-human animals. Here, we tested whether oral administration of the putative anxiolytic probiotic strains Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces the striking increase in anxiety-like behavior and changes in gut microbiota observed following social defeat stress in Syrian hamsters. We administered the probiotic at two different doses for 21 days, and 16S rRNA gene amplicon sequencing revealed a shift in microbial structure following probiotic administration at both doses, independently of stress. Probiotic administration at either dose increased anti-inflammatory cytokines IL-4, IL-5, and IL-10 compared to placebo. Surprisingly, probiotic administration at the low dose, equivalent to the one used in humans, significantly increased social avoidance and decreased social interaction. This behavioral change was associated with a reduction in microbial richness in this group. Together, these results demonstrate that probiotic administration alters gut microbial composition and may promote an anti-inflammatory profile but that these changes may not promote reductions in behavioral responses to social stress.

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