scholarly journals Sensitization to Chronic Stress-Induced Depression and Anxiety Modulated by Gut-Brain-Axis Immunity

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1174-1174
Author(s):  
Giulio Pasinetti
Keyword(s):  
Chronic Stress ◽  
Brain Regions ◽  
Multivariate Adaptive Regression Splines ◽  
Depression And Anxiety ◽  
Behavioral Impairment ◽  
Funding Sources ◽  
Adaptive Immune Cells ◽  
Promising Therapeutic Target ◽  
Adaptive Regression ◽  
Neuro Inflammation

Abstract Objectives Chronic stress manifests as depressive- and anxiety-like impairments while recurrent stress elicits disproportionate psychiatric responses linked to stress-induced immunological priming. The microbiota-gut-brain-axis is a promising therapeutic target for stress-induced behavioral impairment as it simultaneous alters the immunological landscape of the periphery and brain by modulating innate and adaptive immune cells’ activity at barrier sites. Methods Immunophenotyping of the ileum, spleen and PBMCs verified that the synbiotic's impact on ileal barrier immunity, and not inflammatory or microglial activation in limbic brain regions, best associated to stress- and synbiotic-induced behavioral responses via the microbiota-ILC3-Treg axis. A multivariate adaptive regression splines (MARS) analysis predicted that immune responses in the brain and periphery create a cross-tissue biological signature of stress-induced behavior. Ileal and splenic IL-1 and IL-6 release and the ileal Treg/Th17 cell ratio associated to limbic chemotactic chemokine and prefrontal cortex IL-1 release, which associated to behavioral deficits. Results In this study, a combination of probiotics and prebiotics (i.e., synbiotic) promoted behavioral resilience to chronic and recurrent stress by promoting regulatory T cell (Treg) activation and reducing the T helper (Th)17 to Treg ratio by modulating ileal innate lymphoid cell (ILC)3 activity. Synbiotics also normalized gut microbiome diversity and composition in response to stress while interactions of the genera Lactobacillus with Faecalibaculum, Blautia or Bifidobacterium spp. best associated to depressive-like behavior during the stress protocol. Conclusions This analysis shows how resilience to stress-induced behavioral impairment depends on the gut-brain-axis and that synbiotics indiscriminately attenuate peripheral- and neuro-inflammation associated with chronic and recurrent stress-induced depression and anxiety. Funding Sources Grant AT008661 from the NIH's ODS and the NCCIH.

scholarly journals Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Susan Westfall ◽  
Francesca Caracci ◽  
Molly Estill ◽  
Tal Frolinger ◽  
Li Shen ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Behavioral Responses ◽  
Depression And Anxiety ◽  
Behavioral Impairment ◽  
Behavioral Deficits ◽  
Machine Learning Model ◽  
Promising Therapeutic Target ◽  
Behavioral Impairments ◽  
Better Than ◽  
Immunological Priming

Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.

scholarly journals Flavonoids Ameliorate Stress-Induced Depression by Preventing NLRP3 Inflammasome Priming

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1231-1231
Author(s):  
Giulio Pasinetti
Keyword(s):  
Mrna Expression ◽  
Chronic Stress ◽  
Nlrp3 Inflammasome ◽  
Signaling Cascades ◽  
Dietary Polyphenols ◽  
Funding Sources ◽  
Glycation End Products ◽  
Molecular Patterns

Abstract Objectives Chronic stress activates danger-associated molecular patterns (DAMPs), stimulating the NLRP3 inflammasome. NLRP3 activation triggers the release of pro-inflammatory cytokine IL-1β. The activity of the NLRP3 inflammasome propagates pro-inflammatory signaling cascades implicated in the onset of depression. Our previous studies show that polyphenolic compounds were found to ameliorate stress induced depression in mouse models. However, the relevant mechanism has not been identified. This study examined the effect of administering polyphenols on DAMP signaling in enriched mice microglia. Methods This study examined the effect of administering polyphenols on DAMP signaling in mice microglia. To recapitulate stress-induced depression, mice underwent chronic unpredictable stress (CUS). Microglia were isolated at various time points throughout the CUS protocol. We also assessed long-term persistent changes after CUS and susceptibility to subthreshold unpredictable stress (US) re-exposure. Results Interestingly, the development of US – induced depression and anxiety depended upon a previous exposure to CUS. We found that CUS caused robust upregulation of IL-1β mRNA in enriched microglia, an effect that persists for up to 4 weeks following CUS exposure. Following the subthreshold US re-exposure, we observed the upregulation of pro- IL-1β as well as pro-receptor for advanced glycation end products (RAGE). Toll-like receptor 4 (TLR-4) was not. We also observed an increase in RAGE mRNA expression when mice were exposed to US prior to the start of the CUS paradigm. Importantly, a primary exposure to US, was sufficient to increase RAGE mRNA expression. We found that polyphenol administration significantly improved CUS-induced depressive-like phenotypes and also reversed neuroinflammation in mice. Treatment with dietary flavonoids prevented upregulation of IL-1β, RAGE mRNA, which reflects the ability of polyphenols that may have begun following the primary exposure to US. Conclusions Taken all together, the results provide evidence of the role of dietary polyphenols in preventing persistent microglial activation, which has been shown to result in reduced long term vulnerability to depressive-like behaviors following expose to chronic stress. Funding Sources This study was supported by a P50 CARBON Center grant from the NCCIH/ODS.

Prediction of transportation energy demand: Multivariate Adaptive Regression Splines

Energy ◽  
2021 ◽  
Vol 224 ◽  
pp. 120090
Author(s):  
Mohammad Ali Sahraei ◽  
Hakan Duman ◽  
Muhammed Yasin Çodur ◽  
Ecevit Eyduran
Keyword(s):  
Energy Demand ◽  
Multivariate Adaptive Regression Splines ◽  
Regression Splines ◽  
Transportation Energy ◽  
Adaptive Regression ◽  
Adaptive Regression Splines

scholarly journals Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery

2021 ◽  
Author(s):  
Dorota Zolkowska ◽  
Chun-Yi Wu ◽  
Michael A. Rogawski
Keyword(s):  
Adverse Effects ◽  
Screen Test ◽  
Brain Regions ◽  
Seizure Threshold ◽  
Brain Delivery ◽  
Intranasal Delivery ◽  
Behavioral Impairment ◽  
Loss Of Righting Reflex ◽  
Ptz Test ◽  
Central Nervous System Activity

AbstractAllopregnanolone, a positive modulator of GABAA receptors with antiseizure activity, has potential in the treatment of seizure emergencies. Instillation of allopregnanolone in 40% sulfobutylether-β-cyclodextrin into the nose in mice rapidly elevated the seizure threshold in the timed intravenous pentylenetetrazol (ED50, 5.6 mg/kg), picrotoxin (ED50, 5.9 mg/kg), and bicuculline seizure tests. The effect peaked at 15 min, decayed over 1 h, and was still evident in some experiments at 6 h. Intranasal allopregnanolone also delayed the onset of seizures in the maximal PTZ test. At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. In addition, intranasal allopregnanolone failed to cause loss-of-righting reflex in most animals, but when the same dose was administered intramuscularly, all animals became impaired. Intranasal allopregnanolone (10 mg/kg) caused a rapid increase in brain allopregnanolone with a Tmax of ~5 min after initiation of the intranasal delivery. High levels of allopregnanolone were recovered in the olfactory bulb (Cmax, 16,000 ng/mg) whereas much lower levels (Cmax, 670 ng/mg) were present in the remainder of the brain. We conclude that the unique ability of intranasal allopregnanolone to protect against seizures without inducing behavioral adverse effects is due in part to direct nose-to-brain delivery, with preferential transport to brain regions relevant to seizures. Benzodiazepines are commonly administered intranasally for acute seizure therapy, including for the treatment of acute repetitive seizures, but are not transported from nose-to-brain. Intranasal allopregnanolone acts with greater speed, has less propensity for adverse effects, and has the ability to overcome benzodiazepine refractoriness. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications.

scholarly journals COVID-19 pandemic related long-term chronic stress on the prevalence of depression and anxiety in the general population

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tian Qi ◽  
Ting Hu ◽  
Qi-Qi Ge ◽  
Xiao-Na Zhou ◽  
Jia-Mei Li ◽  
...  
Keyword(s):  
Mental Health ◽  
General Population ◽  
Chronic Stress ◽  
Protective Factor ◽  
Mental Health Problems ◽  
Anxiety Symptoms ◽  
Binary Logistic Regression Analysis ◽  
Depression And Anxiety ◽  
Factors Associated

Abstract Background The COVID-19 pandemic has lasted for more than 1 year, causing far-reaching and unprecedented changes in almost all aspects of society. This study aimed to evaluate the long-term consequences of the COVID-19 pandemic on depression and anxiety, and explore the factors associated with it. Methods A cross-sectional study using an online survey was conducted to assess mental health problems from February 2 to February 9, 2021 by using patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder-7 (GAD-7). The insomnia severity index (ISI), demographic data and COVID-19 related variables were measured by a self-designed questionnaire. The factors associated with depressive and anxiety symptoms were identified by Pearson chi-square test and binary logistic regression analysis. Results In the study that 1171 participants enrolled, the overall prevalence of depressive and anxiety symptoms among general people was 22.6 and 21.4% respectively in the present study. Living alone was a potential risk factor for depressive symptoms, while regular exercises was a potential protective factor. The prevalence of depressive and anxiety symptoms was significantly associated with the severity of insomnia symptoms and the negative feelings about pandemic. Conclusion COVID-19 pandemic- related chronic stress has brought about profound impacts on long-term mental health in the general population. The level of insomnia and a negative attitude towards the pandemic are significantly correlated with unfavorable mental health. However, we failed to found a significant association of age and gender with the mental health symptoms, although they were recognized as well-established risk factors during the outbreak by some other studies. This discrepancy may be because the acute and chronic effects of the pandemic are influenced by different factors, which reminds that more attention should be paid to the intrinsic psychological factors and physical reactions towards COVID-19.

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