scholarly journals From stress to depression: Development of extracellular matrix-dependent cognitive impairment following social stress

2019 ◽  
Author(s):  
Maija-Kreetta Koskinen ◽  
Yvar van Mourik ◽  
August Benjamin Smit ◽  
Danai Riga ◽  
Sabine Spijker
Keyword(s):  
Extracellular Matrix ◽  
Cognitive Impairment ◽  
Social Stress ◽  
Molecular Mechanisms ◽  
Recovery Period ◽  
Transition Process ◽  
Hippocampal Function ◽  
Early Stress ◽  
Affective Deficits ◽  
Depressive Episodes

AbstractStress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. To shed light on this stress-to-depression transition process, we profiled the development of an enduring depressive-like state in rat by assessing affective behavior and hippocampal function during the 2 months following social defeat stress. In addition, we measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during a sustained depressive-like state. We found affective disturbance and cognitive impairment to develop disparately after social stress. While affective deficits emerged gradually, spatial memory impairment was present both early after stress and during the late-emerging chronic depressive-like state. Surprisingly, these phases were separated by a period of normalized hippocampal function. Similarly, the SDPS paradigm induced a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Early after stress, synaptic ECM proteins and the number of perineuronal nets enwrapping parvalbumin-expressing interneurons were decreased. This was followed by a recovery period without ECM dysregulation, before subsequent decreased metalloproteinase activity and ECM build-up, previously shown to impair memory. This suggests that intact hippocampal function requires unaltered ECM levels. Together our data 1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, 2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and 3) support a role of the ECM in mediating long-lasting memory-effects of social stress.

scholarly journals From stress to depression: development of extracellular matrix-dependent cognitive impairment following social stress

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maija-Kreetta Koskinen ◽  
Yvar van Mourik ◽  
August Benjamin Smit ◽  
Danai Riga ◽  
Sabine Spijker
Keyword(s):  
Extracellular Matrix ◽  
Cognitive Impairment ◽  
Social Stress ◽  
Molecular Mechanisms ◽  
Cognitive Impairments ◽  
Point Of View ◽  
Early Stress ◽  
Affective Deficits ◽  
Underlying Mechanisms ◽  
Depressive Episodes

Abstract Stress can predispose to depressive episodes, yet the molecular mechanisms regulating the transition from the initial stress response to a persistent pathological depressive state remain poorly understood. We profiled the development of an enduring depressive-like state by assessing affective behavior and hippocampal function during the 2 months following social-defeat stress. We measured remodeling of hippocampal extracellular matrix (ECM) during this period, as we recently identified ECM changes to mediate cognitive impairment during the sustained depressive-like state. Affective disturbance and cognitive impairments develop disparately after social stress, with gradual appearance of affective deficits. In contrast, spatial memory was impaired both early after stress and during the late-emerging chronic depressive-like state, while intact in-between. Similarly, we observed a biphasic regulation of the hippocampal ECM coinciding with hippocampus-dependent memory deficits. Together our data (1) reveal a dichotomy between affective and cognitive impairments similar to that observed in patients, (2) indicate different molecular processes taking place during early stress and the chronic depressive-like state, and (3) support a role of the ECM in mediating long-lasting effects on memory. From a translational point of view, it is important to prioritize on temporal phenotypic aspects in animal models to elucidate the underlying mechanisms of depression.

scholarly journals Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

2021 ◽  
Vol 22 (11) ◽  
pp. 5619
Author(s):  
Iris Ribitsch ◽  
Andrea Bileck ◽  
Alexander D. Aldoshin ◽  
Maciej M. Kańduła ◽  
Rupert L. Mayer ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Tendon Healing ◽  
Tendon Injury ◽  
Inflammatory Factors ◽  
Large Animal ◽  
Post Injury ◽  
Tendon Regeneration ◽  
Large Animal Models

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.

Cellular modulation by the elasticity of biomaterials

2016 ◽  
Vol 4 (1) ◽  
pp. 9-26 ◽  
Author(s):  
Fengxuan Han ◽  
Caihong Zhu ◽  
Qianping Guo ◽  
Huilin Yang ◽  
Bin Li
Keyword(s):  
Extracellular Matrix ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Matrix Elasticity ◽  
Recent Advances

The elasticity of the extracellular matrix has been increasingly recognized as a dominating factor of cell fate and activities. This review provides an overview of the general principles and recent advances in the field of matrix elasticity-dependent regulation of a variety of cellular activities and functions, the underlying biomechanical and molecular mechanisms, as well as the pathophysiological implications.

Abstract MP254: Decellularized Extracellular Matrix Hydrogel Lowers Fibrosis And Fibroblast Differentiation In Post-injury Mice Hearts Through Capg

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Xinming Wang ◽  
Samuel Senyo
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Smooth Muscle Actin ◽  
Growth Factor Receptor ◽  
Inhibitory Effect ◽  
Extracellular Proteins ◽  
Collagen Deposition ◽  
Post Injury ◽  
Capping Protein ◽  
Decellularized Extracellular Matrix

Hypothesis and objective: We hypothesize that transplantation of decellularized cardiac extracellular matrix (dECM) lowers fibrosis and fibroblast differentiation. In this study we investigated collagen deposition and fibroblast differentiation in post-MI hearts and heart explants of various stiffness after dECM hydrogel treatments. The objectives are 1) determining if dECM derived from fetal and adult porcine hearts reduces fibrosis in injured hearts; and 2) identifying specific signaling pathways that regulate fibroblasts differentiation induced by extracellular proteins. Methods: Porcine dECM was injected immediately after ligating coronary artery in P1 mice. Histology was conducted on day 7 post-myocardial infarction (MI). A mice ventricle explant model was used to investigate the molecular mechanisms. Results: We observed that fetal dECM treatment lowered fibrosis and fibroblast differentiation in post-MI hearts (Fig.1). Fibroblast differentiation as indicated by α-smooth muscle actin expression in vimentin or platelet derived growth factor receptor α positive cells showed an inhibitory effect of fetal dECM on fibroblast differentiation. Using a heart explant model of modulated microenvironment stiffness, we demonstrated that increasing tissue stiffness stimulates fibroblast differentiation and collagen deposition. Fetal dECM treatment, however, inhibited fibroblast differentiation induced by increasing microenvironment stiffness. Transcriptome analysis revealed that two cytoskeleton-related genes, macrophage capping protein (CAPG) and leupaxin (LPXN), are modulated by dECM treatments. Using cytoskeleton polymerization modulators and siRNA, we demonstrated that fetal dECM lowers fibroblast differentiation through CAPG.

scholarly journals miR-98-5p plays a critical role in depression and antidepressant effect of ketamine

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Chaoli Huang ◽  
Yuanyuan Wang ◽  
Zifeng Wu ◽  
Jiali Xu ◽  
Ling Zhou ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Social Stress ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Rapid Onset ◽  
Therapeutic Strategies ◽  
Antidepressant Effect ◽  
Depression Treatment ◽  
Chronic Social Stress ◽  
Beneficial Effects

AbstractKetamine has been demonstrated to be a rapid-onset and long-lasting antidepressant, but its underlying molecular mechanisms remain unclear. Recent studies have emerged microRNAs as important modulators for depression treatment. In this study, we report that miR-98-5p is downregulated in the prefrontal cortex and hippocampus of mice subjected to chronic social stress, while overexpressing it by its agonist alleviates depression-like behaviors. More importantly, we demonstrate that miR-98-5p is upregulated by ketamine administration, while inhibition of it by its antagonist blocks the antidepressant effect of ketamine. Our data implicate a novel molecular mechanism underlying the antidepressant effect of ketamine, and that therapeutic strategies targeting miR-98-5p could exert beneficial effects for depression treatment.

scholarly journals Application of rhythmic transcranial magnetic stimulation with low-intensive running pulsed magnetic field in the rehabilitation of patients with post-stroke cognitive impairment syndrome

2020 ◽  
Vol 12 (2) ◽  
pp. 51-62
Author(s):  
Alexey Е. Tereshin ◽  
Vera V. Kiryanova ◽  
Dmitry A. Reshetnik ◽  
Marina V. Karyagina ◽  
Elena K. Savelyeva ◽  
...  
Keyword(s):  
Magnetic Field ◽  
Cognitive Impairment ◽  
Transcranial Magnetic Stimulation ◽  
Magnetic Stimulation ◽  
Modulation Frequency ◽  
Recovery Period ◽  
Pulsed Magnetic Field ◽  
Control Group ◽  
Early Recovery ◽  
Post Stroke

The purpose of the investigation was to study the nootropic effects of rhythmic transcranial magnetic stimulation (rTMS) using low-intensity magnetic field with the induction rate of 45 mT, base frequency of 50 Hz, modulation frequency of 10 Hz in combination with standard medical and psychological therapy in the rehabilitation of patients with post-stroke cognitive impairment (PSCI). Materials and methods. The rehabilitation outcomes in 98 patients with PSCI syndrome were studied. The patients were subdivided into 2 groups: 53 patients of the control group were treated with the standard nootropic medications and neuropsychological procedures; 45 patients of the main group were additionally treated with rTMS by the low-intensive running pulsed magnetic field of 10 Hz modulation frequency. The dynamics of the score increase according to Rivermid, Karnovsky, Roshina, MMSE, mRS, HDRS, SF-36 scales were analyzed. Conclusion. Application of rTMS with low-intensive running pulsed magnetic field of 10 Hz modulation frequency in combination with a standard program of cognitive rehabilitation contributes to a significant improvement in the recovery of mental calculation function in ischemic stroke patients, as well as normalization in mood swings in the patients who had suffered a hemorrhagic stroke and post-stroke depression. This variant of rTMS can be safely used in patients with PSCI syndrome in the early recovery period, 3 weeks after the onset of stroke.

Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials

2018 ◽  
Vol 10 (422) ◽  
pp. eaao0475 ◽  
Author(s):  
Marsha C. Lampi ◽  
Cynthia A. Reinhart-King
Keyword(s):  
Extracellular Matrix ◽  
Clinical Trials ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Therapeutic Interventions ◽  
Target Tissue ◽  
Matrix Stiffness ◽  
Extracellular Matrix Stiffness

Tissues stiffen during aging and during the pathological progression of cancer, fibrosis, and cardiovascular disease. Extracellular matrix stiffness is emerging as a prominent mechanical cue that precedes disease and drives its progression by altering cellular behaviors. Targeting extracellular matrix mechanics, by preventing or reversing tissue stiffening or interrupting the cellular response, is a therapeutic approach with clinical potential. Major drivers of changes to the mechanical properties of the extracellular matrix include phenotypically converted myofibroblasts, transforming growth factor β (TGFβ), and matrix cross-linking. Potential pharmacological interventions to overcome extracellular matrix stiffening are emerging clinically. Aside from targeting stiffening directly, alternative approaches to mitigate the effects of increased matrix stiffness aim to identify and inhibit the downstream cellular response to matrix stiffness. Therapeutic interventions that target tissue stiffening are discussed in the context of their limitations, preclinical drug development efforts, and clinical trials.

Lysyl oxidases: from enzyme activity to extracellular matrix cross-links

2019 ◽  
Vol 63 (3) ◽  
pp. 349-364 ◽  
Author(s):  
Sylvain D. Vallet ◽  
Sylvie Ricard-Blum
Keyword(s):  
Extracellular Matrix ◽  
Molecular Mechanisms ◽  
Catalytic Domain ◽  
Lysyl Oxidase ◽  
Dimensional Structure ◽  
Cross Linking ◽  
Copper Binding ◽  
Molecular Features ◽  
Ecm Proteins ◽  
Cross Links

Abstract The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase like proteins (LOXL1-4). They are copper amine oxidases with a highly conserved catalytic domain, a lysine tyrosylquinone cofactor, and a conserved copper-binding site. They catalyze the first step of the covalent cross-linking of the extracellular matrix (ECM) proteins collagens and elastin, which contribute to ECM stiffness and mechanical properties. The role of LOX and LOXL2 in fibrosis, tumorigenesis, and metastasis, including changes in their expression level and their regulation of cell signaling pathways, have been extensively reviewed, and both enzymes have been identified as therapeutic targets. We review here the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans, and by inhibitors. We also make an overview of the major ECM cross-links, because they are the ultimate molecular readouts of LOX/LOXL activity in tissues. The recent 3D model of LOX, which recapitulates its known structural and biochemical features, will be useful to decipher the molecular mechanisms of LOX interaction with its various substrates, and to design substrate-specific inhibitors, which are potential antifibrotic and antitumor drugs.

scholarly journals Obesity-induced Cognitive Impairment in Older Adults: a Microvascular Perspective

2020 ◽  
Author(s):  
Priya Balasubramanian ◽  
Tamas Kiss ◽  
Stefano Tarantini ◽  
Ádám Nyúl-Tóth ◽  
Chetan Ahire ◽  
...  
Keyword(s):  
United States ◽  
Cognitive Impairment ◽  
Molecular Mechanisms ◽  
Epidemiological Data ◽  
The Elderly ◽  
The United States ◽  
Potential Contribution ◽  
Blood Brain Barrier Disruption ◽  
Brain Barrier Disruption ◽  
Microvascular Rarefaction

Over two thirds of individuals aged 65 and older are obese or overweight in the United States. Epidemiological data show an association between the degree of adiposity and cognitive dysfunction in the elderly. In this review, the pathophysiological roles of microvascular mechanisms, including impaired endothelial function and neurovascular coupling responses, microvascular rarefaction and blood-brain barrier disruption in the genesis of cognitive impairment in geriatric obesity are considered. The potential contribution of adipose-derived factors and fundamental cellular and molecular mechanisms of senescence to exacerbated obesity-induced cerebromicrovascular impairment and cognitive decline in aging are discussed.

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