scholarly journals Roles of multiple lipid mediators in stress and depression

2019 ◽  
Vol 31 (9) ◽  
pp. 579-587 ◽  
Author(s):  
Tomoyuki Furuyashiki ◽  
Satoshi Akiyama ◽  
Shiho Kitaoka
Keyword(s):  
Chronic Stress ◽  
Social Defeat ◽  
Lipid Mediators ◽  
Mental Illnesses ◽  
Lipid Mediator ◽  
Receptor Subtype ◽  
Social Defeat Stress ◽  
Beneficial Effects ◽  
Prostaglandin Synthase ◽  
Depressive Patients

AbstractProlonged or excessive stress may induce emotional and cognitive disturbances, and is a risk factor for mental illnesses. Using rodent chronic stress models of depression, roles of multiple lipid mediators related to inflammation have been revealed in chronic stress-induced emotional alterations. Prostaglandin (PG) E2, an arachidonic acid (AA)-derived lipid mediator, and its receptor subtype EP1 mediate depression-like behavior induced by repeated social defeat stress through attenuating prefrontal dopaminergic activity. Repeated social defeat stress activates microglia through innate immune receptors, and induces PGE2 synthesis through cyclooxygenase-1, a prostaglandin synthase enriched in microglia. PGD2, another AA-derived lipid mediator, has been implicated in depression induced by chronic stress, although either pro-depressive or anti-depressive actions have been reported. Chronic stress up-regulates hippocampal expression of 5-lipoxygenase, hence synthesis of cysteinyl leukotrienes, thereby inducing depression through their receptors. Consistent with beneficial effects of n-3 fatty acids in the diet of depressive patients, resolvins—a novel class of pro-resolving lipid mediators—in the brain attenuate neuroinflammation-associated depression. These findings in animal models of depression offer lipid mediators and related molecules as novel therapeutic targets for treating depression. To translate these findings into clinics, translational biomarkers to visualize lipid mediator profiles in depressive patients need to be established.

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

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.

scholarly journals Chronic non-discriminatory social defeat stress reduces effort-related motivated behaviors in male and female mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Andrew Dieterich ◽  
Tonia Liu ◽  
Benjamin Adam Samuels
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Choice Behavior ◽  
Progressive Ratio ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Male And Female ◽  
Female Mice ◽  
High Reward ◽  
Motivated Behaviors

AbstractReward and motivation deficits are prominent symptoms in many mood disorders, including depression. Similar reward and effort-related choice behavioral tasks can be used to study aspects of motivation in both rodents and humans. Chronic stress can precipitate mood disorders in humans and maladaptive reward and motivation behaviors in male rodents. However, while depression is more prevalent in women, there is relatively little known about whether chronic stress elicits maladaptive behaviors in female rodents in effort-related motivated tasks and whether there are any behavioral sex differences. Chronic nondiscriminatory social defeat stress (CNSDS) is a variation of chronic social defeat stress that is effective in both male and female mice. We hypothesized that CNSDS would reduce effort-related motivated and reward behaviors, including reducing sensitivity to a devalued outcome, reducing breakpoint in progressive ratio, and shifting effort-related choice behavior. Separate cohorts of adult male and female C57BL/6 J mice were divided into Control or CNSDS groups, exposed to the 10-day CNSDS paradigm, and then trained and tested in instrumental reward or effort-related behaviors. CNSDS reduced motivation to lever press in progressive ratio and shifted effort-related choice behavior from a high reward to a more easily attainable low reward in both sexes. CNSDS caused more nuanced impairments in outcome devaluation. Taken together, CNSDS induces maladaptive shifts in effort-related choice and reduces motivated lever pressing in both sexes.

scholarly journals LIMK1/2 in the mPFC Plays a Role in Chronic Stress-Induced Depressive-Like Effects in Mice

2020 ◽  
Vol 23 (12) ◽  
pp. 821-836
Author(s):  
Ting-Ting Gao ◽  
Yuan Wang ◽  
Ling Liu ◽  
Jin-Liang Wang ◽  
Ying-Jie Wang ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Restraint Stress ◽  
Social Defeat ◽  
Mild Stress ◽  
Chronic Unpredictable Mild Stress ◽  
Chronic Restraint Stress ◽  
Lim Domain ◽  
Social Defeat Stress ◽  
Chronic Social Defeat Stress ◽  
Pharmacological Target

Abstract Background Depression is one of the most common forms of mental illness and also a leading cause of disability worldwide. Developing novel antidepressant targets beyond the monoaminergic systems is now popular and necessary. LIM kinases, including LIM domain kinase 1 and 2 (LIMK1/2), play a key role in actin and microtubule dynamics through phosphorylating cofilin. Since depression is associated with atrophy of neurons and reduced connectivity, here we speculate that LIMK1/2 may play a role in the pathogenesis of depression. Methods In this study, the chronic unpredictable mild stress (CUMS), chronic restraint stress (CRS), and chronic social defeat stress (CSDS) models of depression, various behavioral tests, stereotactic injection, western blotting, and immunofluorescence methods were adopted. Results CUMS, CRS, and CSDS all significantly enhanced the phosphorylation levels of LIMK1 and LIMK2 in the medial prefrontal cortex (mPFC) but not the hippocampus of mice. Administration of fluoxetine, the most commonly used selective serotonin reuptake inhibitor in clinical practice, fully reversed the effects of CUMS, CRS, and CSDS on LIMK1 and LIMK2 in the mPFC. Moreover, pharmacological inhibition of LIMK1 and LIMK2 in the mPFC by LIMKi 3 infusions notably prevented the pro-depressant effects of CUMS, CRS, and CSDS in mice. Conclusions In summary, these results suggest that LIMK1/2 in the mPFC has a role in chronic stress-induced depressive-like effects in mice and could be a novel pharmacological target for developing antidepressants.

scholarly journals Chronic Social Defeat Stress Modulates Dendritic Spines Structural Plasticity in Adult Mouse Frontal Association Cortex

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Yu Shu ◽  
Tonghui Xu
Keyword(s):  
Prefrontal Cortex ◽  
Chronic Stress ◽  
Neural Circuits ◽  
Neural Circuit ◽  
Structural Plasticity ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Chronic Social Defeat Stress ◽  
Stress Experience ◽  
Spine Dynamics

Chronic stress is associated with occurrence of many mental disorders. Previous studies have shown that dendrites and spines of pyramidal neurons of the prefrontal cortex undergo drastic reorganization following chronic stress experience. So the prefrontal cortex is believed to play a key role in response of neural system to chronic stress. However, how stress induces dynamic structural changes in neural circuit of prefrontal cortex remains unknown. In the present study, we examined the effects of chronic social defeat stress on dendritic spine structural plasticity in the mouse frontal association (FrA) cortexin vivousing two-photon microscopy. We found that chronic stress altered spine dynamics in FrA and increased the connectivity in FrA neural circuits. We also found that the changes in spine dynamics in FrA are correlated with the deficit of sucrose preference in defeated mice. Our findings suggest that chronic stress experience leads to adaptive change in neural circuits that may be important for encoding stress experience related memory and anhedonia.

scholarly journals Chronic stress impairs male spermatogenesis function and nectin-3 protein expression in the testis

2020 ◽  
pp. 297-306
Author(s):  
T. Li ◽  
J. Yao ◽  
Q. Zhang ◽  
Q. Li ◽  
J. Li ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Molecular Mechanisms ◽  
Social Defeat ◽  
Histological Structure ◽  
Male Mice ◽  
Corticotropin Releasing Hormone ◽  
Social Defeat Stress ◽  
Control Male ◽  
Releasing Hormone ◽  
Chronic Social Defeat Stress

Chronic stress is a crucial public issue that occurs when a person is repetitively stimulated by various stressors. Previous researches have reported that chronic stress induces spermatogenesis dysfunction in the reproductive system, but its molecular mechanisms remain unclear. The nectin protein family, including nectin-1 to nectin-4, is Ca(2+)-independent immunoglobulin-like cell adhesion molecules, that are widely expressed in the hippocampus, testicular tissue, epithelial cells and other sites. Nectin-3 contributes to the sperm development at the late stage, and the abnormal expression of nectin-3 impairs spermatogenesis. Some recent studies have demonstrated that stress induces a decrease in nectin-3 expression in the hippocampus via corticotropin-releasing hormone (CRH) to corticotropin-releasing hormone receptor 1 (CRHR1) pathway. Here, we tested whether chronic stress also caused a reduction in nectin-3 expression in the testis. We established a chronic social defeat stress paradigm, which provides naturalistic and complex chronic stress in male C57BL/6 mice. After 25 days of chronic social defeat stress, the mice showed weight loss, thymic atrophy and some other typical symptoms of chronic stress (e.g. anxiety-like behavior and social avoidance behavior). We found gonad atrophy, testicular histological structure changes and semen quality reductions in the stressed mice. The stressed male mice significantly spent more time to impregnate the female mice than the control male mice. Moreover, nectin-3 protein levels in stressed mice were significantly decreased in the testes compared with those in control mice. In addition, we found that the CRHR1 expression level was increased in the testes of stressed mice. Therefore, we demonstrated a decreased level of nectin-3 expression and an increase in CRHR1 expression in the testis after exposure to chronic stress, which may provide a potential therapeutic target for the spermatogenesis dysfunction induced by chronic stress.

scholarly journals Splenic NKG2D confers resilience versus susceptibility in mice after chronic social defeat stress: beneficial effects of (R)-ketamine

2019 ◽  
Author(s):  
Kai Zhang ◽  
Akemi Sakamoto ◽  
Lijia Chang ◽  
Youge Qu ◽  
Siming Wang ◽  
...  
Keyword(s):  
Psychiatric Disorders ◽  
Molecular Mechanisms ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Beneficial Effects ◽  
Nkg2d Expression ◽  
Chronic Social Defeat Stress ◽  
Group 2 ◽  
Stress Susceptibility

AbstractThe spleen is a large immune organ that plays a key role in the immune system. The precise molecular mechanisms underlying the relationship between the spleen and stress-related psychiatric disorders are unknown. Here we investigated the role of spleen in stress-related psychiatric disorders. FACS analysis was applied to determine the contribution of the spleen to susceptibility and resilience in mice that were subjected to chronic social defeat stress (CSDS). We found a notable increase in splenic volume and weight in CSDS-susceptible mice compared to control (no CSDS) mice and CSDS-resilient mice. The number of granulocytes, but not of T cells and B cells, in the spleen of susceptible mice was higher than in the spleen of both control and resilient mice. Interestingly, NKG2D (natural killer group 2, member D) expression in the spleen of CSDS-susceptible mice was higher than that in control mice and CSDS-resilient mice. In addition, NKG2D expression in the spleen of patients with depression was higher than that in controls. Both increased splenic weight and increased splenic NKG2D expression in CSDS-susceptible mice were ameliorated after a subsequent administration of (R)-ketamine. The present findings indicate a novel role of splenic NKG2D in stress susceptibility versus resilience in mice subjected to CSDS. Furthermore, abnormalities in splenic functions in CSDS-susceptible mice were ameliorated after subsequent injection of (R)-ketamine. Thus, the brain–spleen axis might, at least in part, contribute to the pathogenesis of stress-related psychiatric disorders such as depression.

scholarly journals Histone Lysine Demethylase JMJD2D/KDM4D and Family Members Mediate Effects of Chronic Social Defeat Stress on Mouse Hippocampal Neurogenesis and Mood Disorders

2020 ◽  
Vol 10 (11) ◽  
pp. 833
Author(s):  
Swati Maitra ◽  
Nitin Khandelwal ◽  
Scherazad Kootar ◽  
Pooja Sant ◽  
Salil S. Pathak ◽  
...  
Keyword(s):  
Mood Disorders ◽  
Chronic Stress ◽  
Social Defeat ◽  
Social Defeat Stress ◽  
Histone Lysine ◽  
Chronic Social Defeat Stress ◽  
Proliferation And Differentiation ◽  
Lysine Residues ◽  
Induced Changes

Depression, anxiety and related mood disorders are major psychiatric illnesses worldwide, and chronic stress appears to be one of the primary underlying causes. Therapeutics to treat these debilitating disorders without a relapse are limited due to the incomplete molecular understanding of their etiopathology. In addition to the well-studied genetic component, research in the past two decades has implicated diverse epigenetic mechanisms in mediating the negative effects of chronic stressful events on neural circuits. This includes the cognitive circuitry, where the dynamic hippocampal dentate gyrus (DG) neurogenesis gets affected in depression and related affective disorders. Most of these epigenetic studies have focused on the impact of acetylation/deacetylation and methylation of several histone lysine residues on neural gene expression. However, there is a dearth of investigation into the role of demethylation of these lysine residues in chronic stress-induced changes in neurogenesis that results in altered behaviour. Here, using the chronic social defeat stress (CSDS) paradigm to induce depression and anxiety in C57BL/6 mice and ex vivo DG neural stem/progenitor cell (NSCs/NPCs) culture we show the role of the members of the JMJD2/KDM4 family of histone lysine demethylases (KDMs) in mediating stress-induced changes in DG neurogenesis and mood disorders. The study suggests a critical role of JMJD2D in DG neurogenesis. Altered enrichment of JMJD2D on the promoters of Id2 (inhibitor of differentiation 2) and Sox2 (SRY-Box Transcription Factor 2) was observed during proliferation and differentiation of NSCs/NPCs obtained from the DG. This would affect the demethylation of repressive epigenetic mark H3K9, thus activating or repressing these and possibly other genes involved in regulating proliferation and differentiation of DG NSCs/NPCs. Treatment of the NSCs/NPCs culture with Dimethyloxallyl Glycine (DMOG), an inhibitor of JMJDs, led to attenuation in their proliferation capacity. Additionally, systemic administration of DMOG in mice for 10 days induced depression-like and anxiety-like phenotype without any stress exposure.

scholarly journals Leucine–Histidine Dipeptide Attenuates Microglial Activation and Emotional Disturbances Induced by Brain Inflammation and Repeated Social Defeat Stress

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2161 ◽  
Author(s):  
Yasuhisa Ano ◽  
Masahiro Kita ◽  
Shiho Kitaoka ◽  
Tomoyuki Furuyashiki
Keyword(s):  
Inflammatory Cytokines ◽  
Social Defeat ◽  
Emotional Disturbances ◽  
Mental Illnesses ◽  
Brain Inflammation ◽  
Fermented Foods ◽  
Social Defeat Stress ◽  
Number Of Patients ◽  
The Brain ◽  
Pro Inflammatory Cytokines

The number of patients with mental illnesses is rapidly increasing, and daily lifestyle is closely associated with the development of symptoms. It is suggested that inflammatory molecules derived from microglia play crucial roles for the pathophysiology of depression. In the present study, we discovered that leucine–histidine (LH) dipeptide suppressed activation of primary microglia. The effects of LH dipeptide orally administered were measured using tail suspension test (TST) in mice injected with lipopolysaccharide and social interaction test in mice received social defeat stress. LH dipeptide reduced pro-inflammatory cytokines upon stimulation in microglia. Orally administered LH dipeptide was delivered to the brain and suppressed the production of pro-inflammatory cytokines in the brain and concomitant depression-like behavior in the TST. Moreover, oral administration of LH dipeptide suppressed the induction of depression- and anxiety-like behaviors induced by repeated social defeat stress. These results indicate that LH dipeptide suppressed the activation of microglia and ameliorated depression-associated emotional disturbances. Further, we found that LH dipeptide was abundant in various fermented products. Together with previous epidemiological reports that daily intake of these fermented foods is negatively associated with the incidence of psychiatric diseases, our findings suggest that food rich in LH dipeptide may improve mental health.

scholarly journals Non-coding enhancer RNA regulates NPAS4 in the mPFC to control chronic stress-induced anhedonia-like behavior

2021 ◽  
Author(s):  
Brandon W Hughes ◽  
Benjamin M Siemsen ◽  
Stefano Berto ◽  
Jaswinder Kumar ◽  
Rebecca G Cornbrooks ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Dendritic Spine ◽  
Social Defeat ◽  
Sucrose Preference ◽  
Social Avoidance ◽  
Spine Density ◽  
Rna Seq ◽  
Social Defeat Stress ◽  
Dendritic Spine Density ◽  
Reward Motivation

Abstract Background: Chronic stress can produce reward system deficits (i.e. anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain poorly understood. Methods: C57BL/6 adult male mice were subjected to chronic social defeat stress (CSDS). Neuronal PAS domain-containing protein 4 (NPAS4) or the Npas4 lnc-eRNA were reduced using a viral-mediated shRNA approach. CSDS-induced behaviors, including social avoidance, sucrose preference, natural reward motivation, and anxiety-like behavior, were then measured. CSDS-induced changes in mPFC dendritic spine density were assessed using confocal imaging, and the mPFC NPAS4-regulated transcriptome was assessed using RNA-seq analysis. Results: Social defeat stress induced transient expression of NPAS4 in the mPFC. Viral-mediated knockdown of mPFC NPAS4 blocked CSDS-induced reduction in sucrose preference and changes in natural reward motivation, but without influencing social avoidance. NPAS4 was also required for CSDS-induced reduction of pyramidal neuron dendritic spine density in mPFC. RNA-seq analysis from mPFC tissues revealed that NPAS4 influences expression of numerous genes linked to glutamatergic synapses and ribosomal function, and to genes dysregulated in multiple neuropsychiatric disorders, including depression. Finally, we found that stress-induced expression of NPAS4 in mPFC requires a novel, activity-regulated lnc-eRNA, and that this Npas4 lnc-eRNA in mPFC was required for CSDS-induced anhedonia-like behavior. Conclusion: Together our findings reveal a novel, stress-regulated and lnc-eRNA-dependent transcriptional mechanism in the mPFC that promotes dendritic spine loss and development of anhedonia-like behaviors.

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