640 research outputs found
Microglial memory of early life stress and inflammation: Susceptibility to neurodegeneration in adulthood
No full textWe review evidence supporting the role of early life programming in the susceptibility for adult neurodegenerative diseases while highlighting questions and proposing avenues for future research to advance our understanding of this fundamental process. The key elements of this phenomenon are chronic stress, neuroinflammation triggering microglial polarization, microglial memory and their connection to neurodegeneration. We review the mediating mechanisms which may function as early biomarkers of increased susceptibility for neurodegeneration. Can we devise novel early life modifying interventions to steer developmental trajectories to their optimum?.Fil: Desplats, Paula. University of California; Estados UnidosFil: Gutierrez, Ashley M.. University of California; Estados UnidosFil: Antonelli, Marta Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Frasch, Martin G.. University of Washington; Estados Unido
Theoretical value of deceleration capacity points to deceleration reserve of fetal heart rate
No full textObjective: The interpretation of Average Acceleration and Deceleration Capacities (AC/DC), computed through Phase-Rectified Signal Averaging (PRSA), in intrapartum fetal heart rate (FHR) monitoring is still matter of investigation. We aimed to elucidate some behaviours of AC/DC. Methods: We derived the theoretical value of PRSA for stationary stochastic Gaussian processes and proved that for these time series AC and DC are necessarily identical in absolute value. The difference between DC and AC, termed Deceleration Reserve (DR), was introduced to detect signals' asymmetric trends. DR was tested on FHR signals from: near-term pregnant sheep model of labor consisting of chronically hypoxic and normoxic fetuses with both groups developing acidemia due to umbilical cord occlusions (UCO); and the CTU-UHB dataset containing fetal CTG recordings collected during labor of newborns that resulted acidotic and non-acidotic, respectively. DR was compared with AC and DC in terms of discriminatory power (AUC), between the groups, after correcting for signals' power or deceleration area, respectively. Results: DR displayed higher discriminatory power on the animal model during severe acidemia, with respect to AC/DC (p<0.05$ but also distinguished correctly all chronically hypoxic from normoxic fetuses at baseline prior to UCO. DR also outperformed AC/DC on the CTU-UHB dataset in distinguishing acidemic fetuses at birth (AUC: 0.65). Conclusion: Theoretical results motivated the introduction of DR, that proved to be superior than AC/DC for risk stratification during labor. Significance: DR, measured during labor, might permit to distinguish acidemic fetuses due to their different autonomic regulation, paving the way for new monitoring strategies
Relationship Between Deceleration Morphology and Phase Rectified Signal Averaging-Based Parameters During Labor
No full textDuring labor, uterine contractions trigger the response of the autonomic nervous system (ANS) of the fetus, producing sawtooth-like decelerations in the fetal heart rate (FHR) series. Under chronic hypoxia, ANS is known to regulate FHR differently with respect to healthy fetuses. In this study, we hypothesized that such different ANS regulation might also lead to a change in the FHR deceleration morphology. The hypothesis was tested in an animal model comprising nine normoxic and five chronically hypoxic fetuses that underwent a protocol of umbilical cord occlusions (UCOs). Deceleration morphologies in the fetal inter-beat time interval (FRR) series were modeled using a trapezoid with four parameters, i.e., baseline b, deceleration depth a, UCO response time τu and recovery time τr. Comparing normoxic and hypoxic sheep, we found a clear difference for τu (24.8±9.4 vs. 39.8±9.7 s; p < 0.05), a (268.1±109.5 vs. 373.0±46.0 ms; p < 0.1) and Δτ = τu − τr (13.2±6.9 vs. 23.9±7.5 s; p < 0.05). Therefore, the animal model supported the hypothesis that hypoxic fetuses have a longer response time τu and larger asymmetry Δτ as a response to UCOs. Assessing these morphological parameters during labor is challenging due to non-stationarity, phase desynchronization and noise. For this reason, in the second part of the study, we quantified whether acceleration capacity (AC), deceleration capacity (DC), and deceleration reserve (DR), computed through Phase-Rectified Signal Averaging (PRSA, known to be robust to noise), were correlated with the morphological parameters. DC, AC and DR were correlated with τu, τr and Δτ for a wide range of the PRSA parameter T (Pearson's correlation ρ > 0.8, p < 0.05). In conclusion, deceleration morphologies have been found to differ between normoxic and hypoxic sheep fetuses during UCOs. The same difference can be assessed through PRSA based parameters, further motivating future investigations on the translational potential of this methodology on human data
Animal Models of Fetal Programming: Focus on Chronic Maternal Stress During Pregnancy and Neurodevelopment
No full textAnimal models of fetal programming contribute in three synergistic ways to understanding and treating human diseases or predispositions to diseases, which emerge from in utero insults leading to fetal programming. Firstly, animal models serve to confirm observationsderived in epidemiological studies. Secondly, animal models provide insights into mechanisms and render novel putative biomarkers of various effects of fetal programming that are relevant for early identification of affected individuals, children and adults. Thirdly, animal models permit testing of therapeutic interventions before they are translated into clinical intervention studies.Fil: Frasch, Martin Gerbert. University of Washington; Estados UnidosFil: Schulkin, Jay A.. University of Washington; Estados UnidosFil: Metz, Gerlinde A. S.. University of Lethbridge; CanadáFil: Antonelli, Marta Cristina. Universidad de Buenos Aires. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin
Surveillance non invasive de la réponse neuroimmunitaire fœtale à l’infection
No full textIntroduction. In utero, l’infection des membranes maternelles et fœtales, la chorioamniotite, passe souvent inaperçue et, en particulier lorsque associée à une acidémie, due à l’occlusion du cordon ombilical (OCO), comme il se produirait au cours du travail, peut entrainer des lésions cérébrales et avoir des répercussions neurologiques péri - et postnatales à long terme chez le fœtus. Il n'existe actuellement aucun moyen de détecter précocement ces conditions pathologiques in utéro afin de prévenir ou de limiter ces atteintes.
Hypothèses. 1)l’électroencéphalogramme (EEG) fœtal obtenu du scalp fœtal pourrait servir d’outil auxiliaire à la surveillance électronique fœtale du rythme cardiaque fœtal (RCF) pour la détection précoce d'acidémie fœtale et d'agression neurologique; 2) la fréquence d’échantillonnage de l’ECG fœtal (ECGf) a un impact important sur le monitoring continu de la Variabilité du Rythme Cardiaque (VRCf) dans la prédiction de l’acidémie fœtale ; 3) les patrons de la corrélation de la VRCf aux cytokines pro-inflammatoires refléteront les états de réponses spontanées versus inflammatoires de la Voie Cholinergique Anti-inflammatoire (VCA); 4) grâce au développement d’un modèle de prédictions mathématiques, la prédiction du pH et de l’excès de base (EB) à la naissance sera possible avec seulement une heure de monitoring d’ECGf.
Méthodes. Dans une série d’études fondamentales et cliniques, en utilisant respectivement le mouton et une cohorte de femmes en travail comme modèle expérimental et clinique , nous avons modélisé 1) une situation d’hypoxie cérébrale résultant de séquences d’occlusion du cordon ombilical de sévérité croissante jusqu’à atteindre un pH critique limite de 7.00 comme méthode expérimentale analogue au travail humain pour tester les première et deuxième hypothèses 2) un inflammation fœtale modérée en administrant le LPS à une autre cohorte animale pour vérifier la troisième hypothèse et 3) un modèle mathématique de prédictions à partir de paramètres et mesures validés cliniquement qui permettraient de déterminer les facteurs de prédiction d’une détresse fœtale pour tester la dernière hypothèse.
Résultats. Les séries d’OCO répétitives se sont soldés par une acidose marquée (pH artériel 7.35±0.01 à 7.00±0.01), une diminution des amplitudes à l'électroencéphalogramme( EEG) synchronisé avec les décélérations du RCF induites par les OCO accompagnées d'une baisse pathologique de la pression artérielle (PA) et une augmentation marquée de VRCf avec hypoxie-acidémie aggravante à 1000 Hz, mais pas à 4 Hz, fréquence d’échantillonnage utilisée en clinique. L’administration du LPS entraîne une inflammation systémique chez le fœtus avec les IL-6 atteignant un pic 3 h après et des modifications de la VRCf retraçant précisément ce profil temporel des cytokines. En clinique, avec nos cohortes originale et de validation, un modèle statistique basée sur une matrice de 103 mesures de VRCf (R2 = 0,90, P < 0,001) permettent de prédire le pH mais pas l’EB, avec une heure d’enregistrement du RCF avant la poussée.
Conclusions. La diminution de l'amplitude à l'EEG suggère un mécanisme d'arrêt adaptatif neuroprotecteur du cerveau et suggère que l'EEG fœtal puisse être un complément utile à la surveillance du RCF pendant le travail à haut risque chez la femme. La VRCf étant capable de détecter une hypoxie-acidémie aggravante tôt chez le fœtus à 1000Hz vs 4 Hz évoque qu’un mode d'acquisition d’ECG fœtal plus sensible pourrait constituer une solution. Des profils distinctifs de mesures de la VRCf, identifiés en corrélation avec les niveaux de l'inflammation, ouvre une nouvelle voie pour caractériser le profil inflammatoire de la réponse fœtale à l’infection. En clinique, un monitoring de chevet de prédiction du pH et EB à la naissance, à partir de mesures de VRCf permettrait des interprétations visuelles plus explicites pour des prises de décision plus exactes en obstétrique au cours du travail.Introduction. In utero, the infection of maternal and fetal membranes, chorioamnionitis, goes frequently unnoticed and, especially when combined with acidemia due to occlusions of the umbilical cord as they occur during labour, can result in brain damage and long term neurological sequelae peri- and postnatally. Currently, there is no way to early detect these pathological conditions to prevent or limit lasting neurological deficits.
Hypotheses. (1) the fetal electroencephalogram (EEG), obtained from the scalp could serve as a useful ancillary tool to the existing fetal heart rate (FHR) monitoring for early detection of fetal acidemia and neurological injury; (2) the sampling rate of fetal ECG has a significant impact on the continuous FHR monitoring in the prediction of fetal acidemia; 3) patterns of FHR variability will reflect fetal baseline and inflammatory states; (4) FHR variability analysis should permit prediction of pH and base excess (BE) at birth.
Methods. In a series of studies using the chronically instrumented unanesthetized fetal sheep and clinical cohort, we modeled 1) worsening fetal acidemia with intermittent hypoxia resulting from umbilical cord occlusions (UCO) of increasing severity as experimental model of human labour to test the 1st and 2nd hypotheses; 2) moderate fetal inflammation by administering lipopolysaccharide (LPS) to test the 3rd hypothesis and 3) prediction of pH and BE status at birth using clinically validated FHR variability measures in a clinical cohort of laboring women to test the 4th hypothesis.
Results. Repetitive UCO resulted in marked acidosis (pH arterial 7.35±0.01 to 7.00±0.01), decreased EEG amplitudes synchronized with UCO-induced FHR decelerations and pathological arterial blood pressure decreases; in addition, we detected a significant increase in FHR variability with worsening acidemia when sampled at 1000 but not at 4 Hz, the sampling rate used clinically. LPS administration resulted in systemic fetal inflammation with IL-6 peaking at 3 h and FHR variability changes tracking this temporal cytokine profile precisely. In the clinical cohort, a statistical model based on a matrix of 103 FHR variability measures predicted pH (R2 = 0.90, P < 0.001), but not BE, from one hour of FHR recording prior to pushing stage.
Conclusions. The decrease in the EEG amplitude suggests an adaptive and neuroprotective brain shut-down; fetal EEG may complement the FHR monitoring during labour to improve early detection of incipient acidemia. FHR variability changes can detect early developing hypoxic-acidemia when sampled at 1000 Hz, but not when sampled at 4 Hz suggesting that a more sensitive mode of fetal ECG acquisition will improve early acidemia detection. Distinctive subsets of FHR variability measures permit online monitoring of fetal inflammation from ECG opening a new approach to characterizing the fetal inflammatory profile. Clinical bedside prediction of pH and BE monitoring at birth using FHR variability monitoring will allow more accurate decision making in obstetrics during labou
Safety of human-AI cooperative decision-making within intensive care: a physical simulation study
No full textThe safety of Artificial Intelligence (AI) systems is as much one of human decision-making as a technological question. In AI-driven decision support systems, particularly in high-stakes settings such as healthcare, ensuring the safety of human-AI interactions is paramount, given the potential risks of following erroneous AI recommendations. To explore this question, we ran a safety-focused clinician-AI interaction study in a physical simulation suite. Physicians were placed in a simulated intensive care ward, with a human nurse (played by an experimenter), an ICU data chart, a high-fidelity patient mannequin and an AI recommender system on a display. Clinicians were asked to prescribe two drugs for the simulated patients suffering from sepsis and wore eye-tracking glasses to allow us to assess where their gaze was directed. We recorded clinician treatment plans before and after they saw the AI treatment recommendations, which could be either ‘safe’ or ‘unsafe’. 92% of clinicians rejected unsafe AI recommendations vs 29% of safe ones. Physicians paid increased attention (+37% gaze fixations) to unsafe AI recommendations vs safe ones. However, visual attention on AI explanations was not greater in unsafe scenarios. Similarly, clinical information (patient monitor, patient chart) did not receive more attention after an unsafe versus safe AI reveal suggesting that the physicians did not look back to these sources of information to investigate why the AI suggestion might be unsafe. Physicians were only successfully persuaded to change their dose by scripted comments from the bedside nurse 5% of the time. Our study emphasises the importance of human oversight in safety-critical AI and the value of evaluating human-AI systems in high-fidelity settings that more closely resemble real world practice
Surveillance non invasive de la réponse neuroimmunitaire fœtale à l’infection
No full textIntroduction. In utero, l’infection des membranes maternelles et fœtales, la chorioamniotite, passe souvent inaperçue et, en particulier lorsque associée à une acidémie, due à l’occlusion du cordon ombilical (OCO), comme il se produirait au cours du travail, peut entrainer des lésions cérébrales et avoir des répercussions neurologiques péri - et postnatales à long terme chez le fœtus. Il n'existe actuellement aucun moyen de détecter précocement ces conditions pathologiques in utéro afin de prévenir ou de limiter ces atteintes.
Hypothèses. 1)l’électroencéphalogramme (EEG) fœtal obtenu du scalp fœtal pourrait servir d’outil auxiliaire à la surveillance électronique fœtale du rythme cardiaque fœtal (RCF) pour la détection précoce d'acidémie fœtale et d'agression neurologique; 2) la fréquence d’échantillonnage de l’ECG fœtal (ECGf) a un impact important sur le monitoring continu de la Variabilité du Rythme Cardiaque (VRCf) dans la prédiction de l’acidémie fœtale ; 3) les patrons de la corrélation de la VRCf aux cytokines pro-inflammatoires refléteront les états de réponses spontanées versus inflammatoires de la Voie Cholinergique Anti-inflammatoire (VCA); 4) grâce au développement d’un modèle de prédictions mathématiques, la prédiction du pH et de l’excès de base (EB) à la naissance sera possible avec seulement une heure de monitoring d’ECGf.
Méthodes. Dans une série d’études fondamentales et cliniques, en utilisant respectivement le mouton et une cohorte de femmes en travail comme modèle expérimental et clinique , nous avons modélisé 1) une situation d’hypoxie cérébrale résultant de séquences d’occlusion du cordon ombilical de sévérité croissante jusqu’à atteindre un pH critique limite de 7.00 comme méthode expérimentale analogue au travail humain pour tester les première et deuxième hypothèses 2) un inflammation fœtale modérée en administrant le LPS à une autre cohorte animale pour vérifier la troisième hypothèse et 3) un modèle mathématique de prédictions à partir de paramètres et mesures validés cliniquement qui permettraient de déterminer les facteurs de prédiction d’une détresse fœtale pour tester la dernière hypothèse.
Résultats. Les séries d’OCO répétitives se sont soldés par une acidose marquée (pH artériel 7.35±0.01 à 7.00±0.01), une diminution des amplitudes à l'électroencéphalogramme( EEG) synchronisé avec les décélérations du RCF induites par les OCO accompagnées d'une baisse pathologique de la pression artérielle (PA) et une augmentation marquée de VRCf avec hypoxie-acidémie aggravante à 1000 Hz, mais pas à 4 Hz, fréquence d’échantillonnage utilisée en clinique. L’administration du LPS entraîne une inflammation systémique chez le fœtus avec les IL-6 atteignant un pic 3 h après et des modifications de la VRCf retraçant précisément ce profil temporel des cytokines. En clinique, avec nos cohortes originale et de validation, un modèle statistique basée sur une matrice de 103 mesures de VRCf (R2 = 0,90, P < 0,001) permettent de prédire le pH mais pas l’EB, avec une heure d’enregistrement du RCF avant la poussée.
Conclusions. La diminution de l'amplitude à l'EEG suggère un mécanisme d'arrêt adaptatif neuroprotecteur du cerveau et suggère que l'EEG fœtal puisse être un complément utile à la surveillance du RCF pendant le travail à haut risque chez la femme. La VRCf étant capable de détecter une hypoxie-acidémie aggravante tôt chez le fœtus à 1000Hz vs 4 Hz évoque qu’un mode d'acquisition d’ECG fœtal plus sensible pourrait constituer une solution. Des profils distinctifs de mesures de la VRCf, identifiés en corrélation avec les niveaux de l'inflammation, ouvre une nouvelle voie pour caractériser le profil inflammatoire de la réponse fœtale à l’infection. En clinique, un monitoring de chevet de prédiction du pH et EB à la naissance, à partir de mesures de VRCf permettrait des interprétations visuelles plus explicites pour des prises de décision plus exactes en obstétrique au cours du travail.Introduction. In utero, the infection of maternal and fetal membranes, chorioamnionitis, goes frequently unnoticed and, especially when combined with acidemia due to occlusions of the umbilical cord as they occur during labour, can result in brain damage and long term neurological sequelae peri- and postnatally. Currently, there is no way to early detect these pathological conditions to prevent or limit lasting neurological deficits.
Hypotheses. (1) the fetal electroencephalogram (EEG), obtained from the scalp could serve as a useful ancillary tool to the existing fetal heart rate (FHR) monitoring for early detection of fetal acidemia and neurological injury; (2) the sampling rate of fetal ECG has a significant impact on the continuous FHR monitoring in the prediction of fetal acidemia; 3) patterns of FHR variability will reflect fetal baseline and inflammatory states; (4) FHR variability analysis should permit prediction of pH and base excess (BE) at birth.
Methods. In a series of studies using the chronically instrumented unanesthetized fetal sheep and clinical cohort, we modeled 1) worsening fetal acidemia with intermittent hypoxia resulting from umbilical cord occlusions (UCO) of increasing severity as experimental model of human labour to test the 1st and 2nd hypotheses; 2) moderate fetal inflammation by administering lipopolysaccharide (LPS) to test the 3rd hypothesis and 3) prediction of pH and BE status at birth using clinically validated FHR variability measures in a clinical cohort of laboring women to test the 4th hypothesis.
Results. Repetitive UCO resulted in marked acidosis (pH arterial 7.35±0.01 to 7.00±0.01), decreased EEG amplitudes synchronized with UCO-induced FHR decelerations and pathological arterial blood pressure decreases; in addition, we detected a significant increase in FHR variability with worsening acidemia when sampled at 1000 but not at 4 Hz, the sampling rate used clinically. LPS administration resulted in systemic fetal inflammation with IL-6 peaking at 3 h and FHR variability changes tracking this temporal cytokine profile precisely. In the clinical cohort, a statistical model based on a matrix of 103 FHR variability measures predicted pH (R2 = 0.90, P < 0.001), but not BE, from one hour of FHR recording prior to pushing stage.
Conclusions. The decrease in the EEG amplitude suggests an adaptive and neuroprotective brain shut-down; fetal EEG may complement the FHR monitoring during labour to improve early detection of incipient acidemia. FHR variability changes can detect early developing hypoxic-acidemia when sampled at 1000 Hz, but not when sampled at 4 Hz suggesting that a more sensitive mode of fetal ECG acquisition will improve early acidemia detection. Distinctive subsets of FHR variability measures permit online monitoring of fetal inflammation from ECG opening a new approach to characterizing the fetal inflammatory profile. Clinical bedside prediction of pH and BE monitoring at birth using FHR variability monitoring will allow more accurate decision making in obstetrics during labou
Ex vivo biomechanical comparison of 4 suture materials for laparoscopic bladder closure in the horse
No full textObjective: To compare a knotless, barbed suture to standard suture using laparoscopic suturing methods in an ex vivo model of equine bladder repair.
Study design: Cadaveric study.
Sample population: Equine cadaver bladders (n=42).
Methods: A 5-cm incision was created and repaired in a laparoscopic training box with 4 different suture materials. Groups 1 and 2 used 2-0 poliglecaprone and 2-0 glycomer knotless, barbed suture, respectively, placed using laparoscopic instruments. Groups 3 and 4 used 0 and 2-0 polyglyconate knotless, barbed suture, respectively, placed using an automated laparoscopic suturing device. All groups used a double-layer inverting pattern. Time for suture placement was recorded. Bladders were inflated with water and bursting strength pressures recorded, including a control group of intact bladders. Statistical analysis using a linear model and taking into account the unequal variances was followed by a post-hoc Tukey's test. Significance was set at P<.05.
Results: Bursting strength did not vary significantly between treatment groups, but was significantly decreased compared to the control group (P<.001). Time to place the sutures with the 2 automated suture device groups (groups 3 and 4) was significantly faster than those in which the suture was placed using laparoscopic needle holders and forceps (groups 1 and 2; P=.001).
Conclusion: Knotless, barbed suture may be a viable alternative to standard suture material for laparoscopic closure of the urinary bladder in horses. Further cyclic and in vivo testing should be performed before use in clinical cases
Regularity of Fetal HRV changes in an In-vivo Sheep Model of Labor
No full textLabor exposes the fetus to repetitive transient hypoxic stress. We assessed whether such events modify the regularity of the fetal inter-beat interval series (fRR), using an in-vivo near-term sheep model, by means of entropy measures. Umbilical cord occlusions (UCO), from partial to complete, were applied to 7 near-term pregnant sheep. Fetal blood samples were collected at intervals of 20 minutes, to quantify pH, lactate and base deficit (“biomarkers”). Fetal ECG recordings were collected with implanted electrodes and used to derive the fRR series. Sample entropy (SampEn), permutation entropy (PE) and conditional PE (cPE) were estimated for fRR patterns of various lengths m, in each 2.5 minutes-long cycle of occlusion and successive recovery. Entropies’ changes in time, during the course of the experiment, and their relation with the simultaneous values of the biomarkers were evaluated with Spearman’s rank-order correlations. Entropy values decreased during the experimental protocol (rs=-0.62 for SampEn at m = 1, rs=-0.27 for PE at m = 5 and rs=-0.30 for cPE at m = 4; p < 0.05). Correlations with biomarkers were found to be moderate for SampEn (0.49 < |rs| < 0.62; p < 0.05) and weak to moderate for PE and cPE (0.31 < |rs| < 0.54; p < 0.05). Repetitive UCOs changed the regularity of fRR, suggesting a pronounced modulation as first line adaptive response
Fetal microglial phenotype in vitro carries memory of prior in vivo exposure to inflammation
No full textOBJECTIVE: Neuroinflammation in utero may result in life-long neurological disabilities. The molecular mechanisms whereby microglia contribute to this response remain incompletely understood.METHODS: Lipopolysaccharide (LPS) or saline were administered intravenously to non-anesthetized chronically instrumented near-term fetal sheep to model fetal inflammation in vivo. Microglia were then isolated from in vivo LPS and saline (naïve) exposed animals. To mimic the second hit of neuroinflammation, these microglia were then re-exposed to LPS in vitro. Cytokine responses were measured in vivo and subsequently in vitro in the primary microglia cultures derived from these animals. We sequenced the whole transcriptome of naïve and second hit microglia and profiled their genetic expression to define molecular pathways disrupted during neuroinflammation.RESULTS: In vivo LPS exposure resulted in IL-6 increase in fetal plasma 3 h post LPS exposure. Even though not histologically apparent, microglia acquired a pro-inflammatory phenotype in vivo that was sustained and amplified in vitro upon second hit LPS exposure as measured by IL-1β response in vitro and RNAseq analyses. While NFKB and Jak-Stat inflammatory pathways were up regulated in naïve microglia, heme oxygenase 1 (HMOX1) and Fructose-1,6-bisphosphatase (FBP) genes were uniquely differentially expressed in the second hit microglia. Compared to the microglia exposed to LPS in vitro only, the transcriptome of the in vivo LPS pre-exposed microglia showed a diminished differential gene expression in inflammatory and metabolic pathways prior and upon re-exposure to LPS in vitro. Notably, this desensitization response was also observed in histone deacetylases (HDAC) 1, 2, 4, and 6. Microglial calreticulin/LRP genes implicated in microglia-neuronal communication relevant for the neuronal development were up regulated in second hit microglia.DISCUSSION: We identified a unique HMOX1 down and FBP (up) phenotype of microglia exposed to the double-hit suggesting interplay of inflammatory and metabolic pathways. Our findings suggest that epigenetic mechanisms mediate this immunological and metabolic memory of the prior inflammatory insult relevant to neuronal development and provide new therapeutic targets for early postnatal intervention to prevent brain injury.</p
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