scholarly journals NLRP3 Inflammasome Is Involved in Cocaine-Mediated Potentiation on Behavioral Changes in CX3CR1-Deficient Mice

2021 ◽  
Vol 11 (10) ◽  
pp. 963
Author(s):  
Ming-Lei Guo ◽  
Ernest T. Chivero ◽  
Shannon E. Callen ◽  
Shilpa Buch
Keyword(s):  
Drug Addiction ◽  
Nlrp3 Inflammasome ◽  
Life Stress ◽  
Early Life Stress ◽  
Later Life ◽  
Behavioral Changes ◽  
Inflammatory Factor ◽  
Pyrin Domain ◽  
Lysosome Biogenesis ◽  
Underlying Mechanisms

Microglia, the primary immunocompetent cells of the brain, are suggested to play a role in the development of drug addiction. Previous studies have identified the microglia-derived pro-inflammatory factor IL1β can promote the progression of cocaine addiction. Additionally, the activation status of microglia and “two-hit hypothesis” have been proposed in the field of drug addiction to explain how early life stress (ELS) could significantly increase the incidence of drug addiction in later life. However, the mechanisms underlying microglia prime and full activation and their roles in drug addiction remain greatly unexplored. Here, we employed CX3CR1-GFP mice (CX3CR1 functional deficiency, CX3CR1−/−) to explore whether primed microglia could potentiate cocaine-mediated behavioral changes and the possible underlying mechanisms. CX3CR1−/− mice revealed higher hyperlocomotion activity and conditional place preference than wild-type (WT) mice did under cocaine administration. In parallel, CX3CR1−/− mice showed higher activity of NLR family pyrin domain-containing 3 (NLRP3) inflammasome than WT mice. Interestingly, CX3CR1 deficiency itself could prime NLRP3 signaling by increasing the expression of NLPR3 and affect lysosome biogenesis under basal conditions. Taken together, our findings demonstrated that the functional status of microglia could have an impact on cocaine-mediated reward effects, and NLRP3 inflammasome activity was associated with this phenomenon. This study was consistent with the two-hit hypothesis and provided solid evidence to support the involvement of microglia in drug addiction. Targeting the NLRP3 inflammasome may represent a novel therapeutic approach for ameliorating or blocking the development of drug addiction.

scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

scholarly journals Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chi Wang ◽  
Hui Liu ◽  
Kun Li ◽  
Zhen-Zhen Wu ◽  
Chen Wu ◽  
...  
Keyword(s):  
Life Stress ◽  
Structural Modification ◽  
Granule Cells ◽  
Early Life Stress ◽  
Memory Deficits ◽  
Dorsoventral Axis ◽  
Beneficial Effects ◽  
Cognition And Emotion ◽  
Adult Mice ◽  
Underlying Mechanisms

AbstractTouch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.

scholarly journals Does epigenetic ‘memory’ of early-life stress predispose to chronic pain in later life? A potential role for the stress regulator FKBP5

2019 ◽  
Vol 374 (1785) ◽  
pp. 20190283 ◽  
Author(s):  
S. M. Géranton
Keyword(s):  
Chronic Pain ◽  
Life Stress ◽  
Early Life ◽  
Potential Role ◽  
Adult Life ◽  
Early Life Stress ◽  
Later Life ◽  
Stress Axis ◽  
Evolutionarily Conserved ◽  
Early Life Events

Animal behaviours are affected not only by inherited genes but also by environmental experiences. For example, in both rats and humans, stressful early-life events such as being reared by an inattentive mother can leave a lasting trace and affect later stress response in adult life. This is owing to a chemical trace left on the chromatin attributed to so-called epigenetic mechanisms. Such an epigenetic trace often has consequences, sometimes long-lasting, on the functioning of our genes, thereby allowing individuals to rapidly adapt to a new environment. One gene under such epigenetic control is FKBP5 , the gene that encodes the protein FKPB51, a crucial regulator of the stress axis and a significant driver of chronic pain states. In this article, we will discuss the possibility that exposure to stress could drive the susceptibly to chronic pain via epigenetic modifications of genes within the stress axis such as FKBP5 . The possibility that such modifications, and therefore, the susceptibility to chronic pain, could be transmitted across generations in mammals and whether such mechanisms may be evolutionarily conserved across phyla will also be debated. This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.

It Was Not Safe to Feel Angry: Disrupted Early Attachment and the Development of Chronic Pain in Later Life

2017 ◽  
Vol 11 (3) ◽  
pp. 223-241 ◽  
Author(s):  
Frances Sommer Anderson
Keyword(s):  
Chronic Pain ◽  
Life Stress ◽  
Psychological Treatment ◽  
Early Life Stress ◽  
Later Life ◽  
Secure Attachment ◽  
Somatic Pain ◽  
Treatment Techniques ◽  
Mind And Body

Using detailed clinical material from her treatment of three patients referred by physiatrist John E. Sarno, for psychological treatment of chronic pain, Dr Anderson illustrates a relationship between dissociated/repressed affect and the development of chronic musculoskeletal back pain. Sarno, conversant with the fundamentals of psychoanalysis, theorised that the somatic pain, which he termed tension myoneural syndrome (TMS), served as a distraction from emotions that were unbearable. That is, the pain served as a psychological defense or survival tactic. In treatment, the adverse impact of overwhelming physical and emotional experiences on attachment and emotion regulation are identified and discussed. Detailed clinical process, which includes the use of trauma treatment techniques, illuminate how psychological treatment can be used to help patients identify and tolerate feelings associated with early life stress, leading to relief from the somatic pain. Anderson, informed by the psychosomatic theories of Krystal and McDougall and by contemporary attachment theorists, advances the position that the physician as diagnostician functions symbolically as the "parent" who links mind and body, thereby reducing the patient's fear of pain and creating a secure attachment bond. In this secure attachment relationship, the physician "authorises" the patient to experience emotions that were previously disavowed. In the relationship with an empathic relational psychoanalyst, the patient's pain resolves as s/he builds a capacity to identify and tolerate emotions and learns how to use emotions, particularly anger, to enhance relationships and improve their quality of life.

scholarly journals Early-life stress and inflammation: A systematic review of a key experimental approach in rodents

2020 ◽  
Vol 4 ◽  
pp. 239821282097804
Author(s):  
Ethan G. Dutcher ◽  
E.A. Claudia Pama ◽  
Mary-Ellen Lynall ◽  
Shahid Khan ◽  
Menna R. Clatworthy ◽  
...  
Keyword(s):  
Systematic Review ◽  
Life Stress ◽  
Early Life ◽  
Maternal Separation ◽  
Early Life Stress ◽  
Later Life ◽  
Interleukin 10 ◽  
Brain Regions ◽  
Clinical Approach ◽  
Necrosis Factor Alpha

Repeated maternal separation is the most widely used pre-clinical approach to investigate the relationship between early-life chronic stress and its neuropsychiatric and physical consequences. In this systematic review, we identified 46 studies that conducted repeated maternal separation or single-episode maternal separation and reported measurements of interleukin-1b, interleukin-6, interleukin-10, tumour necrosis factor-alpha, or microglia activation and density. We report that in the short-term and in the context of later-life stress, repeated maternal separation has pro-inflammatory immune consequences in diverse tissues. Repeated maternal separation animals exhibit greater microglial activation and elevated pro-inflammatory cytokine signalling in key brain regions implicated in human psychiatric disorders. Notably, repeated maternal separation generally has no long-term effect on cytokine expression in any tissue in the absence of later-life stress. These observations suggest that the elevated inflammatory signalling that has been reported in humans with a history of early-life stress may be the joint consequence of ongoing stressor exposure together with potentiated neural and/or immune responsiveness to stressors. Finally, our findings provide detailed guidance for future studies interrogating the causal roles of early-life stress and inflammation in disorders such as major depression.

scholarly journals Active behaviour during early development shapes glucocorticoid reactivity

2019 ◽  
Author(s):  
Luis A. Castillo-Ramírez ◽  
Soojin Ryu ◽  
Rodrigo J. De Marco
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Developmental Stages ◽  
Early Life Stress ◽  
Later Life ◽  
Stress Axis ◽  
Glucocorticoid Response ◽  
The Central Nervous System ◽  
Response To Stress ◽  
Early Life Events

AbstractGlucocorticoids are the final effectors of the stress axis, with numerous targets in the central nervous system and the periphery. They are essential for adaptation, yet currently it is unclear how early life events program the glucocorticoid response to stress. Here we provide evidence that involuntary swimming at early developmental stages can reconfigure the cortisol response to homotypic and heterotypic stress in larval zebrafish (Danio rerio), also reducing startle reactivity and increasing spontaneous activity as well as energy efficiency during active behaviour. Collectively, these data identify a role of the genetically malleable zebrafish for linking early life stress with glucocorticoid function in later life.

scholarly journals Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

2020 ◽  
Author(s):  
Maralinde R. Abbink ◽  
Janssen M. Kotah ◽  
Lianne Hoeijmakers ◽  
Aline Mak ◽  
Genevieve Yvon-Durocher ◽  
...  
Keyword(s):  
Life Stress ◽  
Early Life ◽  
Amyloid Β ◽  
Early Life Stress ◽  
Later Life ◽  
Amyloid Pathology ◽  
Emerging Risk ◽  
Microglial Response ◽  
The Relationship

Abstract Background Early-life stress (ES) is an emerging risk factor for later-life development of Alzheimer’s disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice, and how these relate to the previously reported amyloid pathology and microglial profile. Methods We induced ES by limiting nesting and bedding material from postnatal days (P) 2-9. We studied in WT mice (at P9, P30 and 6 months) and in APP/PS1 mice (at 4 and 10 months) i) GFAP coverage, cell density and complexity in hippocampus (HPC) and entorhinal cortex (EC); ii) hippocampal gene expression of astrocyte markers; and iii) the relationship between astrocyte, microglia and amyloid markers. Results In WT mice, ES increased GFAP coverage in HPC subregions at P9, and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age. Conclusions Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.

130 Early Developmental Exposure to Stress and Programming of Lifelong Gut and Immune Function

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 69-69
Author(s):  
Adam J Moeser
Keyword(s):  
Life Stress ◽  
Disease Risk ◽  
Early Life Stress ◽  
Later Life ◽  
Developmental Programming ◽  
Postnatal Life ◽  
Critical Periods ◽  
Organ Systems ◽  
High Level ◽  
The Impact

Abstract Prenatal and early postnatal life represents critical periods of development across species for many organ systems including immune, nervous, reproductive, and gastrointestinal systems. A high level of plasticity exists during these periods, and thus maternal and environmental cues including stress, immune stimulation, and nutrition, can alter the normal developmental programming of the fetus and neonate and impact the trajectory for disease risk and productivity across the lifespan. This presentation will focus on the impact of and biological mechanisms by which prenatal and early postnatal stressors, including psychological immune and nutritional stressors, alter the normal developmental programming of the immune, gastrointestinal, and neuroendocrine stress axes in the offspring and how this may link to increased disease risk and reduced productivity across the lifespan in animals and humans. Further, specifically how host factors such as biological sex interact with early life stress to shape gut and systemic neuroimmune development and later life disease risk will be discussed.

scholarly journals Evolutionary conserved neural signature of early life stress affects animal social competence

2018 ◽  
Vol 285 (1871) ◽  
pp. 20172344 ◽  
Author(s):  
Cecilia Nyman ◽  
Stefan Fischer ◽  
Nadia Aubin-Horth ◽  
Barbara Taborsky
Keyword(s):  
Social Competence ◽  
Social Environment ◽  
Life Stress ◽  
Glucocorticoid Receptors ◽  
Molecular Mechanisms ◽  
Cichlid Fish ◽  
Early Life Stress ◽  
Later Life ◽  
Stress Axis ◽  
Molecular Pathway

In vertebrates, the early social environment can persistently influence behaviour and social competence later in life. However, the molecular mechanisms underlying variation in animal social competence are largely unknown. In rats, high-quality maternal care causes an upregulation of hippocampal glucocorticoid receptors ( gr ) and reduces offspring stress responsiveness. This identifies gr regulation as a candidate mechanism for maintaining variation in animal social competence. We tested this hypothesis in a highly social cichlid fish, Neolamprologus pulcher , reared with or without caring parents. We find that the molecular pathway translating early social experience into later-life alterations of the stress axis is homologous across vertebrates: fish reared with parents expressed the glucocorticoid receptor gr1 more in the telencephalon. Furthermore, expression levels of the transcription factor egr-1 (early growth response 1) were associated with gr1 expression in the telencephalon and hypothalamus. When blocking glucocorticoid receptors (GR) with an antagonist, mifepristone (RU486), parent-reared individuals showed more socially appropriate, submissive behaviour when intruding on a larger conspecific's territory. Remarkably, mifepristone-treated fish were less attacked by territory owners and had a higher likelihood of territory takeover. Our results indicate that early social-environment effects on stress axis programming are mediated by an evolutionary conserved molecular pathway, which is causally involved in environmentally induced variation of animal social competence.

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