scholarly journals Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

2021 ◽  
Vol 22 (4) ◽  
pp. 1558
Author(s):  
Katarzyna Chamera ◽  
Ewa Trojan ◽  
Katarzyna Kotarska ◽  
Magdalena Szuster-Głuszczak ◽  
Natalia Bryniarska ◽  
...  
Keyword(s):  
Immune Activation ◽  
Mrna Level ◽  
Poly I:C ◽  
Adult Offspring ◽  
Sprague Dawley ◽  
Maternal Immune Activation ◽  
Polyinosinic:Polycytidylic Acid ◽  
Sprague Dawley Rats ◽  
Tnf Α

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

scholarly journals Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages prevents schizophrenia-relevant phenotypes in adult offspring after maternal immune activation: a role of TrkB signaling

2022 ◽  
Author(s):  
Yunfei Tan ◽  
Yuko Fujita ◽  
Yaoyu Pu ◽  
Lijia Chang ◽  
Youge Qu ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Immune Activation ◽  
Dendritic Spine ◽  
Poly I:C ◽  
Adult Offspring ◽  
Spine Density ◽  
Intermittent Administration ◽  
Maternal Immune Activation ◽  
Dendritic Spine Density

AbstractMaternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant (R)-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of (R)-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of (R)-ketamine. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of (R)-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, (R)-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.

Cardiovascular and renal sympathetic activation by blood-borne TNF-α in rat: the role of central prostaglandins

2003 ◽  
Vol 284 (4) ◽  
pp. R916-R927 ◽  
Author(s):  
Zhi-Hua Zhang ◽  
Shun-Guang Wei ◽  
Joseph Francis ◽  
Robert B. Felder
Keyword(s):  
Lateral Ventricle ◽  
Biological Effects ◽  
Brain Regions ◽  
Ventrolateral Medulla ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Tnf Α ◽  
Hypothalamic Level ◽  
Renal Sympathetic

In pathophysiological conditions, increased blood-borne TNF-α induces a broad range of biological effects, including activation of the hypothalamic-pituitary-adrenal axis and sympathetic drive. In urethane-anesthetized adult Sprague-Dawley rats, we examined the mechanisms by which blood-borne TNF-α activates neurons in paraventricular nucleus (PVN) of hypothalamus and rostral ventrolateral medulla (RVLM), two critical brain regions regulating sympathetic drive in normal and pathophysiological conditions. TNF-α (0.5 μg/kg), administered intravenously or into ipsilateral carotid artery (ICA), activated PVN and RLVM neurons and increased sympathetic nerve activity, arterial pressure, and heart rate. Responses to intravenous TNF-α were not affected by vagotomy but were reduced by mid-collicular decerebration. Responses to ICA TNF-α were substantially reduced by injection of the cyclooxygenase inhibitor ketorolac (150 μg) into lateral ventricle. Injection of PGE2 (50 ng) into lateral ventricle or directly into PVN increased PVN or RVLM activity, respectively, and sympathetic drive, with shorter onset latency than blood-borne TNF-α. These findings suggest that blood-borne cytokines stimulate cardiovascular and renal sympathetic responses via a prostaglandin-dependent mechanism operating at the hypothalamic level.

scholarly journals Prenatal Zinc Supplementation Ameliorates Hippocampal Astrocytes Activation and Inflammatory Cytokines Expression Induced by Lipopolysaccharide in a Rat Model of Maternal Immune Activation

2021 ◽  
Author(s):  
Ebrahim Savareh ◽  
◽  
Nahid Davoodian ◽  
Ronak Mousaviyan ◽  
Maryam Ghasemi-Kasman ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Rat Model ◽  
Immune Activation ◽  
Zinc Supplementation ◽  
Neuroprotective Effect ◽  
Adult Offspring ◽  
Mrna Levels ◽  
Maternal Immune Activation ◽  
Tnf Α ◽  
Hippocampal Astrocytes

Objective: There is evidence that gestational exposure to lipopolysaccharide (LPS) results in fetal zinc deficiency, and eventually neurodevelopmental abnormalities. In this study, we utilized a rat model of maternal immune activation (MIA) to investigate the possible neuroprotective effect of zinc supplementation throughout pregnancy on hippocampal astrocytes activation as well as inflammatory cytokines expression in adult offspring. Methods: Pregnant rats received intraperitoneal injections of either LPS (0.5 mg/kg) or saline at gestational day (GD) 15 and 16 and orally gavaged with zinc sulfate (30 mg/kg) throughout pregnancy. Astrocyte density and histological assessment were evaluated in the hippocampus of adult offspring at postnatal day (PND) 60-62. Also, the mRNA levels of IL-6, TNF-α, IL-1β, NF-κB, and glial fibrillary acidic protein (GFAP) were measured using qPCR analysis. Results: Prenatal exposure to LPS resulted in up-regulated expression levels of IL-6, TNF-α, NF-κB, and GFAP in the hippocampus of adult pups. Moreover, offspring from LPS group showed an increased astrocyte density in CA1 region with no histological alterations in CA1 and CA3 areas. Conversely, maternal zinc supplementation ameliorated these inflammatory alterations induced by LPS. Discussion: This study provides support for the premise that zinc supplementation during pregnancy might be an early treatment option to inhibit hippocampal inflammation induced by the maternal immune response to infectious agents.

scholarly journals Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

eNeuro ◽  
2019 ◽  
Vol 6 (2) ◽  
pp. ENEURO.0437-18.2019 ◽  
Author(s):  
Brittney R. Lins ◽  
Wendie N. Marks ◽  
Nadine K. Zabder ◽  
Quentin Greba ◽  
John G. Howland
Keyword(s):  
Immune Activation ◽  
Female Offspring ◽  
Sprague Dawley ◽  
Maternal Immune Activation ◽  
Sprague Dawley Rats ◽  
Behavior Profile

scholarly journals The Effect of Subdiaphragmatic Vagotomy on Heart Rate Variability and Lung Inflammation in Rats with Severe Hemorrhagic Shock

2021 ◽  
Author(s):  
Fateme Khodadadi ◽  
Farzaneh Ketabchi ◽  
Zahra Khodabandeh ◽  
Alireza Tavassoli ◽  
Gregory F. Lewis ◽  
...  
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Hemorrhagic Shock ◽  
Hemodynamic Parameters ◽  
Sprague Dawley ◽  
Inflammatory Reactions ◽  
Sprague Dawley Rats ◽  
Tnf Α

Abstract Background The role of the sub-diaphragmatic branch of the vagus nerve in mediating heart rate variability (HRV) and inflammatory reaction to long term hemorrhagic shock has not been determined prior to this study. Methods Male Sprague-Dawley rats were divided into four groups of Sham, sub-diaphragmatic vagotomized (Vag), long term (130±2 minutes) hemorrhagic shock (LHS), and sub-diaphragmatic vagotomized with LHS (Vag+LHS). Hemodynamic parameters were recorded and HRV calculated during multiple phases of hemorrhagic shock. The expressions of TNF-α and iNOS were measured in the spleen and lung tissues at the conclusion of the protocol. Results Decreases in blood pressure during blood withdrawal were identical in the LHS and Vag+LHS groups. However, heart rate only decreased in the Nadir-1 phase of the LHS group. HRV indicated increased power in the very-low, low, and high (VLF, LF, and HF) frequency bands during the Nadir-1 phase of the LHS group and decreased power in the Vag+LHS group. There was metabolic acidosis partially compensated with respiratory system in the LHS and Vag+LHS groups. Increases of TNF-α and iNOS expression in the spleen and lung of the LHS group were reversed in the Vag+LHS group. Conclusion This study indicates that sub-diapragmatic vagotomy increases lung inflammatory reactions and blunts the cardiac vagal tone surge in response to severe hemorrhagic shock.

scholarly journals F21. THE PHOSPHODIESTERASE-9 INHIBITOR BI 409306 ATTENUATES SOCIAL INTERACTION AND DOPAMINERGIC DEFICITS IN ADULT OFFSPRING OF POLY(I:C)-BASED MATERNAL IMMUNE ACTIVATION NEURODEVELOPMENTAL MOUSE MODEL

2019 ◽  
Vol 45 (Supplement_2) ◽  
pp. S262-S262
Author(s):  
Juliet Richetto ◽  
Joseph Scarborough ◽  
Roberto Arban ◽  
Cornelia Dorner-Ciossek ◽  
Holger Rosenbrock ◽  
...  
Keyword(s):  
Social Interaction ◽  
Mouse Model ◽  
Immune Activation ◽  
Poly I:C ◽  
Adult Offspring ◽  
Maternal Immune Activation

scholarly journals Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1676
Author(s):  
Katarzyna Chamera ◽  
Magdalena Szuster-Głuszczak ◽  
Ewa Trojan ◽  
Agnieszka Basta-Kaim
Keyword(s):  
Adult Male ◽  
Immune Activation ◽  
Sensorimotor Gating ◽  
Male Offspring ◽  
Sprague Dawley ◽  
Second Hit ◽  
Maternal Immune Activation ◽  
Lps Challenge ◽  
Life Challenges ◽  
Sprague Dawley Rats

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

scholarly journals A Proof-of-Concept Study of Maternal Immune Activation Mediated Induction of Toll-Like Receptor (TLR) and Inflammasome Pathways Leading To Neuroprogressive Changes and Schizophrenia-Like Behaviors in Offspring.

2021 ◽  
Author(s):  
Pinku Mani Talukdar ◽  
Fazal Abdul ◽  
Michael Maes ◽  
Michael Berk ◽  
Ganesan Venkatasubramanian ◽  
...  
Keyword(s):  
Prepulse Inhibition ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Poly I:C ◽  
Sprague Dawley ◽  
Maternal Immune Activation ◽  
Prenatal Infection ◽  
Prenatal Infections ◽  
Apoptotic Pathways ◽  
Few Data

Abstract Infection, particularly prenatal infection leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes in the prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviors through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-1β, IL-6, TNF-α and IL-17A assessed after 24 hours were observed in poly (I:C) and LPS-treated rats, indicating MIA. The offspring rats of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviors, deficits in social behaviors and prepulse inhibition. The hippocampus of offspring rats showed increased expression of TLR3, TLR4, NLRP3, IL-1β, and IL-18 of poly (I:C) and TLR3, TLR4, NLRP3, Cas1, IL-1β, and IL-18 of LPS-treated dams. Notably, the expression of these genes showed a positive correlation with apoptotic and a negative correlation with neuroprotective genes. Furthermore, TLR and inflammasome genes had significant impact on social deficits and impaired prepulse inhibition in offspring rats. The results suggest MIA due to prenatal infection perhaps trigger TLR, inflammasome and apoptotic pathways leading to the induction of schizophrenia-like behaviors in the later stages of life. Prenatal infections seem to drive neuroprogression and subsequently schizophrenia-like symptoms through a common central pathway involving TLR, inflammasome and apoptosis.

Inhibition of phospholipase C-γ1augments the decrease in cardiomyocyte viability by H2O2

2006 ◽  
Vol 291 (2) ◽  
pp. H854-H860 ◽  
Author(s):  
Rabban Mangat ◽  
Tushi Singal ◽  
Naranjan S. Dhalla ◽  
Paramjit S. Tappia
Keyword(s):  
Oxidative Stress ◽  
Phospholipase C ◽  
Mrna Level ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Inhibitory Peptide ◽  
Trypan Blue Exclusion ◽  
Kinase C ◽  
Sprague Dawley Rats

The present study was conducted to examine the role of a major cardiac phospholipase C (PLC) isozyme, PLC-γ1, in cardiomyocytes during oxidative stress. Left ventricular cardiomyocytes were isolated by collagenase digestion from adult male Sprague-Dawley rats (250–300 g) and treated with 20, 50, and 100 μM H2O2for 15 min. A concentration-dependent (up to 50 μM) increase in the mRNA level and membrane protein content of PLC-γ1was observed with H2O2treatment. Furthermore, PLC-γ1was activated in response to H2O2, as revealed by an increase in the phosphorylation of its tyrosine residues. There was a marked increase in the phosphorylation of the antiapoptotic protein Bcl-2 by H2O2; this change was attenuated by a PLC inhibitor, U-73122. Although both protein kinase C (PKC)-δ and -ε protein contents were increased in the cardiomyocyte membrane fraction in response to H2O2, PKC-ε activation, unlike PKC-δ, was attenuated by U-73122 (2 μM). Inhibition of PKC-ε with inhibitory peptide (0.1 μM) prevented Bcl-2 phosphorylation. Moreover, different concentrations (0.05, 0.1, and 0.2 μM) of this peptide augmented the decrease in cardiomyocyte viability in response to H2O2. In addition, a decrease in cardiomyocyte viability, as assessed by trypan blue exclusion, due to H2O2was also seen when cells were pretreated with U-73122 and was as a result of increased apoptosis. It is therefore suggested that PLC-γ1may play a role in cardiomyocyte survival during oxidative stress via PKC-ε and phosphorylation of Bcl-2.

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