Gonadal Hormone Trigger Traf6-mediated Dynamic Microglial Alterations That Correlate With Depressive Symptomatology

Abstract Backgrounds: Gonadal hormone deficiency is associated with the development of depression, but what mediates this association is unclear. To test the possibility that it reflects neuroimmune and neuroinflammatory processes, we analyzed how gonadal hormone deficiency and replacement affect microglial activation and inflammatory response during the development of depressive symptomatology in gonadectomized male mice. Methods: Adult male ICR mice received gonadectomy. Gonadal hormone levels, neuroinflammation, mciroglial activation and depressive behaviors were evaluated 7 days, 14 days, and 30 days later. Furthermore, the neuroprotective mechanism of treatment with testosterone and estradiol on depressive symptomatology were also observed.Results: Testosterone level and the ratio of testosterone to estradiol in the serum and brain tissue of mice exposed to 3-35 days of chronic unpredictable stress were much lower than in control animals. Gonadal hormone sustained deficiency in gonadectomized mice and subsequent led to acute inflammation at day 7 following castration. Activating microglia in mice exposed to 7 days of castration subsequently suppressed the proliferation of microglia, such that their numbers in hippocampus and cortex were lower than the numbers in sham-operated mice after 30 days of castration. Here, we showed that gonadal hormone deficiency induces Traf6-mediated microglia activation, a type of inflammatory mediator. Microglia treated in this way for long time showed down-regulation of activation markers, abnormal morphology and depressive-like behaviors. Restoration and maintenance of a fixed ratio of testosterone to estradiol significantly suppressed microglial activation, neuronal necroptosis, dramatically inducing hippocampal neurogenesis and reducing depressive behaviors via the suppression of Traf6/TAK1 pathway. Conclusions: These findings suggest that activated or immunoreactive microglia contribute to gonadal hormone deficiency-induced depression, as well as testosterone and estradiol exert synergistic anti-depressant effects via suppressing microglial activaton in gonadectomized male mice, possibly through Traf6 signaling.

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Growth hormone deficiency and excess alter the gut microbiome in adult male mice

Yearbook of Paediatric Endocrinology ◽

10.1530/ey.17.4.9 ◽

2020 ◽

Author(s):

Jensen EA ◽

Young JA ◽

Jackson Z ◽

Busken J ◽

List EO ◽

...

Keyword(s):

Growth Hormone ◽

Growth Hormone Deficiency ◽

Adult Male ◽

Gut Microbiome ◽

Hormone Deficiency ◽

Male Mice

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Water-Soluble Arginyl–Diosgenin Analog Attenuates Hippocampal Neurogenesis Impairment Through Blocking Microglial Activation Underlying NF-κB and JNK MAPK Signaling in Adult Mice Challenged by LPS

Molecular Neurobiology ◽

10.1007/s12035-019-1496-3 ◽

2019 ◽

Vol 56 (9) ◽

pp. 6218-6238 ◽

Cited By ~ 2

Author(s):

Bangrong Cai ◽

Kyung-Joo Seong ◽

Sun-Woong Bae ◽

Min Suk Kook ◽

Changju Chun ◽

...

Keyword(s):

Microglial Activation ◽

Mapk Signaling ◽

Hippocampal Neurogenesis ◽

Water Soluble ◽

Adult Mice

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Prion Protein Expression Differences in Microglia and Astroglia Influence Scrapie-Induced Neurodegeneration in the Retina and Brain of Transgenic Mice

Journal of Virology ◽

10.1128/jvi.00865-07 ◽

2007 ◽

Vol 81 (19) ◽

pp. 10340-10351 ◽

Cited By ~ 31

Author(s):

Lisa Kercher ◽

Cynthia Favara ◽

James F. Striebel ◽

Rachel LaCasse ◽

Bruce Chesebro

Keyword(s):

Transgenic Mice ◽

Prion Protein ◽

Microglial Activation ◽

Prion Diseases ◽

Cell Types ◽

Mouse Strains ◽

Activation Markers ◽

Activated Microglia ◽

Morphological Criteria ◽

Scrapie Infection

ABSTRACT Activated microglia and astroglia are known to be involved in a variety of neurodegenerative diseases, including prion diseases. In the present experiments, we studied activation of astroglia and microglia after intraocular scrapie infection in transgenic mice expressing prion protein (PrP) in multiple cell types (tg7 mice) or in neurons only (tgNSE mice). In this model, scrapie infection and protease-resistant PrP deposition occurs in the retinas of both strains of mice, but retinal degeneration is observed only in tg7 mice. Our results showed that the retinas of tg7 and tgNSE mice both had astroglial activation with increased chemokine expression during the course of infection. However, only tg7 retinas exhibited strong microglial activation compared to tgNSE retinas, which showed little microglial activation by biochemical or morphological criteria. Therefore, microglial PrP expression might be required for scrapie-induced retinal microglial activation and damage. Furthermore, microglial activation preceded retinal neurodegeneration in tg7 mice, suggesting that activated microglia might contribute to the degenerative process, rather than being a response to the damage. Surprisingly, brain differed from retina in that an altered profile of microglial activation markers was upregulated, and the profiles in the two mouse strains were indistinguishable. Microglial activation in the brain was associated with severe brain vacuolation and neurodegeneration, leading to death. Thus, retinal and brain microglia appeared to differ in their requirements for activation, suggesting that different activation pathways occur in the two tissues.

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N-Docosahexaenoylethanolamine Attenuates Neuroinflammation and Improves Hippocampal Neurogenesis in Rats with Sciatic Nerve Chronic Constriction Injury

Marine Drugs ◽

10.3390/md18100516 ◽

2020 ◽

Vol 18 (10) ◽

pp. 516 ◽

Cited By ~ 1

Author(s):

Anna A. Tyrtyshnaia ◽

Evgenia L. Egorova ◽

Anna A. Starinets ◽

Arina I. Ponomarenko ◽

Ekaterina V. Ermolenko ◽

...

Keyword(s):

Neuropathic Pain ◽

Microglial Activation ◽

Lipid Analysis ◽

Hippocampal Neurogenesis ◽

Raw Material ◽

Long Term Memory ◽

Inflammatory Factor ◽

Behavioral Experiments ◽

Chronic Neuropathic Pain ◽

The Brain

Chronic neuropathic pain is a condition that causes both sensory disturbances and a variety of functional disorders, indicating the involvement of various brain structures in pain pathogenesis. One of the factors underlying chronic neuropathic pain is neuroinflammation, which is accompanied by microglial activation and pro-inflammatory factor release. N-docosahexaenoylethanolamine (DHEA, synaptamide) is an endocannabinoid-like metabolite synthesized endogenously from docosahexaenoic acid. Synaptamide exhibits anti-inflammatory activity and improves neurite outgrowth, neurogenesis, and synaptogenesis within the hippocampus. This study aims to evaluate the effects of synaptamide obtained by the chemical modification of DHA, extracted from the Far Eastern raw material Berryteuthis magister on neuroinflammatory response and hippocampal neurogenesis changes during neuropathic pain. The study of microglial protein and cytokine concentrations was performed using immunohistochemistry and ELISA. The brain lipid analysis was performed using the liquid chromatography-mass spectrometry technique. Behavioral experiments showed that synaptamide prevented neuropathic pain-associated sensory and behavioral changes, such as thermal allodynia, impaired locomotor activity, working and long-term memory, and increased anxiety. Synaptamide attenuated microglial activation, release of proinflammatory cytokines, and decrease in hippocampal neurogenesis. Lipid analysis revealed changes in the brain N-acylethanolamines composition and plasmalogen concentration after synaptamide administration. In conclusion, we show here that synaptamide may have potential for use in preventing or treating neuropathic cognitive pain and emotional effects.

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Cranial irradiation mediated spine loss is sex-specific and complement receptor-3 dependent in male mice

Scientific Reports ◽

10.1038/s41598-019-55366-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Joshua J. Hinkle ◽

John A. Olschowka ◽

Tanzy M. Love ◽

Jacqueline P. Williams ◽

M. Kerry O’Banion

Keyword(s):

Quality Of Life ◽

Dendritic Spine ◽

Cranial Irradiation ◽

Common Mechanism ◽

Complement Receptor ◽

Spine Density ◽

Male Mice ◽

Activation Markers ◽

Complement Receptor 3

AbstractCranial irradiation is the main therapeutic treatment for primary and metastatic malignancies in the brain. However, cranial radiation therapy produces long-term impairment in memory, information processing, and attention that contribute to a decline in quality of life. The hippocampal neural network is fundamental for proper storage and retrieval of episodic and spatial memories, suggesting that hippocampal signaling dysfunction could be responsible for the progressive memory deficits observed following irradiation. Previous rodent studies demonstrated that irradiation induces significant loss in dendritic spine number, alters spine morphology, and is associated with behavioral task deficits. Additionally, the literature suggests a common mechanism in which synaptic elimination via microglial-mediated phagocytosis is complement dependent and associated with cognitive impairment in aging as well as disease. We demonstrate sexual dimorphisms in irradiation-mediated alterations of microglia activation markers and dendritic spine density. Further, we find that the significant dendritic spine loss observed in male mice following irradiation is microglia complement receptor 3 (CR3)-dependent. By identifying sex-dependent cellular and molecular factors underlying irradiation-mediated spine loss, therapies can be developed to counteract irradiation-induced cognitive decline and improve patient quality of life.

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Thrombin-induced microglial activation impairs hippocampal neurogenesis and spatial memory ability in mice

Behavioral and Brain Functions ◽

10.1186/s12993-015-0075-7 ◽

2015 ◽

Vol 11 (1) ◽

Cited By ~ 25

Author(s):

Yuan Yang ◽

Meikui Zhang ◽

Xiaoni Kang ◽

Chen Jiang ◽

Huan Zhang ◽

...

Keyword(s):

Spatial Memory ◽

Microglial Activation ◽

Hippocampal Neurogenesis ◽

Memory Ability

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Corticosteroid treatment exacerbates bone osteopenia in mice with gonadal hormone deficiency–induced osteoporosis

European Journal of Pharmaceutical Sciences ◽

10.1016/j.ejps.2017.04.023 ◽

2017 ◽

Vol 105 ◽

pp. 41-46 ◽

Cited By ~ 2

Author(s):

Riadh Badraoui ◽

Nahed Amri ◽

Nourhène Zammel ◽

Rim Chaabane ◽

Tarek Rebai

Keyword(s):

Corticosteroid Treatment ◽

Hormone Deficiency ◽

Gonadal Hormone

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Psoralen and Isopsoralen Ameliorate Sex Hormone Deficiency-Induced Osteoporosis in Female and Male Mice

BioMed Research International ◽

10.1155/2016/6869452 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 12

Author(s):

Xiaomei Yuan ◽

Yanan Bi ◽

Zeman Yan ◽

Weiling Pu ◽

Yuhong Li ◽

...

Keyword(s):

Serum Alkaline Phosphatase ◽

Bone Destruction ◽

Hormone Deficiency ◽

Estradiol Valerate ◽

Control Group ◽

Tartrate Resistant Acid Phosphatase ◽

Sham Operation ◽

Type I ◽

Male Mice ◽

Treatment Of Osteoporosis

Osteoporosis is a systemic skeletal disease, which is characterized by a systemic destruction of bone mass and microarchitecture. With life standard improved, the treatment of osteoporosis attracted more attention. The aim of this study is to verify the osteoprotective effect of psoralen and isopsoralen in females and males. Female and male mice were divided into 7 groups in this study: control group (sham-operation), model group (by ovariectomy or orchidectomy), positive control group (females given estradiol valerate; males given alendronate sodium), psoralen groups (10 mg/kg and 20 mg/kg), and isopsoralen groups (10 mg/kg and 20 mg/kg). After administration of psoralen and isopsoralen for 8 weeks, osteoporosis was ameliorated with increasing bone strength and improving trabecular bone microstructure as indicated by CT scan and pathology. Serum alkaline phosphatase (ALP), tartrate resistant acid phosphatase (TRACP), osteocalcin (OC), and C-terminal cross-linking telopeptides of type I collagen (CTX-1) were examined. Decreased TRACP and increased ALP/TRACP suggested restoring from bone destruction. These results suggest that psoralen and isopsoralen may be used as good natural compounds for the treatment of osteoporosis in males, as well as females.

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PACAP and VIP Modulate LPS-induced Microglial Activation and Trigger Distinct Phenotypic Changes in Murine BV2 Microglial Cells

10.20944/preprints202108.0559.v1 ◽

2021 ◽

Author(s):

Jocelyn Karunia ◽

Aram Niaz ◽

Mawj Mandwie ◽

Sarah Thomas Broome ◽

Kevin A Keay ◽

...

Keyword(s):

Cell Migration ◽

Microglial Activation ◽

Activation Markers ◽

Bv2 Cells ◽

Bv2 Microglia ◽

Cell Subpopulations ◽

Underlying Mechanisms ◽

And Migration ◽

Phenotypic Shift ◽

Bv2 Microglial Cells

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally-related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP or VIP differentially affected microglial activation, morphology and cell migration. We found that both peptides attenuated LPS-induced expression of the microglial activation markers Iba1 and iNOS (###p<0.001), as well as the pro-inflammatory mediators IL-1β, IL-6, Itgam and CD68 (###p<0.001). In contrast, treatment with PACAP or VIP exerted distinct effects on microglial morphology and migration. PACAP reversed LPS-induced soma enlargement and increased the percentage of small-sized, rounded cells (54.09% vs 12.05% in LPS-treated cells), whereas VIP promoted a phenotypic shift towards cell subpopulations with mid-sized, spindle-shaped soma (48.41% vs 31.36% in LPS-treated). Additionally, PACAP was more efficient than VIP in restoring LPS-induced impairment of cell migration and the expression of urokinase plasminogen activator (uPA) in BV2 cells compared with VIP. These results suggest that whilst both PACAP and VIP exert similar immunosuppressive effects in activated BV2 microglia, each peptide triggers distinctive shifts towards phenotypes of differing morphologies and with differing migration capacities.

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