Sickness Behavior Score Is Associated with Neuroinflammation and Late Behavioral Changes in Polymicrobial Sepsis Animal Model

Giustina, Amanda Della; Mathias, Khiany; Oliveira, Aloir de; Fileti, Maria Eduarda; Zarbato, Graciela Freitas; Garbossa, Leandro; Rosa, Naiana da; Oliveira, Juliana Medeiros de; Vieira, Andriele; Generoso, Jaqueline S.; Oliveira, Bruna Hoffmann de; Ferreira, Nivaldo; Palandi, Juliete; Bobinski, Franciane; Martins, Daniel Fernandes; Fortunato, Jucélia Jeremias; Barichello, Tatiana; Quevedo, João; Dal‐Pizzol, Felipe; Petronilho, Fabrícia

doi:10.1007/s10753-020-01187-z

Cited by 14 publications

(12 citation statements)

References 64 publications

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“…Although there were no significant differences in various behaviors when individual tests were considered, we were interested in integrating multiple behavioral outcomes into a composite score. This would allow us to characterize offspring behavior holistically, which has been used in multiple areas of research (El-Kordi et al, 2013; Guyenet et al, 2010; Möller et al, 2018; O’Neal, Nooney, Thien, & Ferguson, 2020; Pereira de Souza Goldim et al, 2020; Shahi, Freedman, Dahl, Karandikar, & Mangalam, 2019). The use of a global severity score classification system allows us to examine the distribution of animals’ performance across multiple behavioral tests, where higher values represent higher behavioral symptom severity.…”

Section: Resultsmentioning

confidence: 99%

In utero exposure to morphine leads to sex-specific behavioral alterations that persist into adulthood in cross-fostered mice

Fleites

Markwalter²,

Johnson³

et al. 2022

Preprint

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Introduction: The opioid epidemic has seen an increase in drug use among women of reproductive age. It is well established that Opioid Use Disorder (OUD) can have many negative consequences for the health of mothers and their babies, both during pregnancy and after delivery, but our understanding of the impact of fetal opioid exposure on behavior during adolescence and adulthood is less understood. Preclinical studies have unveiled some of the long-term effects of in utero morphine exposure primarily using injections as the route of drug delivery. Our study utilized a model for oral, voluntary morphine self-administration to investigate neonate, adolescent, and adult offspring behavioral phenotypes and subsequent ethanol misuse liability. Methods: We first validated a paradigm for maternal oral intake of morphine, where female mice became morphine dependent pre-pregnancy, and continued to voluntarily consume morphine in the continuous two-bottle choice (C2BC) paradigm during pregnancy and up to offspring postnatal day 7 (PND 7). Offspring were cross-fostered to a drug-naive dam at PND 7, to model first and second trimester in utero exposure in humans and to mimic the stress associated with NOWS. Bodyweight and ultrasonic vocalizations were assessed to determine alterations in the neonates. Offspring from control and morphine-exposed dams were then tested during adolescence and adulthood in a battery of behavioral tests to assess baseline behavioral phenotypes. We also computed a global behavioral score (GBS) to integrate offspring multiple behavioral outcomes into a composite score that could be used to identify potential vulnerable and resilient populations in offspring exposed prenatally to morphine. Offspring that were tested during adolescence were also evaluated during adulthood in the ethanol intermittent 2BC to assess ethanol misuse risk. Results: Using an oral maternal morphine C2BC protocol, we demonstrated that morphine dams display signs of dependence, measured by somatic signs during withdrawal, and voluntarily drink morphine throughout gestation. Neonate cross-fostered offspring display changes in spontaneous activity, body weight, and ultrasonic vocalization parameters. During adolescence, offspring display both increased baseline anxiety-like/compulsive-like behavior, while in adulthood they display increased anxiety-like behavior. No changes were found for baseline physical signs, locomotion, and depressive-like behavior during adolescence or adulthood. In addition, a greater percentage of adult male offspring exposed to maternal morphine fell into moderate and high GBS classifications, signaling a more severe behavioral phenotype, compared to male control offspring. These effects were not observed in adult female offspring exposed to morphine in utero. Additionally, male adult offspring exposed to maternal morphine reduced their 2-hour ethanol intake in the intermittent two-bottle choice (I2BC) paradigm, although no changes in 24-hour ethanol intake and preference were found. No changes were observed in female offspring of morphine-exposed dams. Conclusion: Overall, maternal morphine exposure leads to sex-specific changes in neonate, adolescent, and adult behavior, including ethanol intake.

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Section: Resultsmentioning

confidence: 99%

In utero exposure to morphine leads to sex-specific behavioral alterations that persist into adulthood in cross-fostered mice

Fleites

Markwalter²,

Johnson³

et al. 2022

Preprint

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“…In the acute stage, state fragmentation presents as many short sleep episodes that are widely distributed across the 24-hour period [18], indicating possible disturbances in both the homeostatic and circadian sleep regulatory systems: changes of central melatonin release rhythms [13], as well as circadian regulation of suprachiasmatic and HPA-axis activity [37][38][39]. Although the main molecular drivers of sleep homeostasis are not yet known, in ammation has been shown to affect expression of BDNF and adenosine 2A receptors [40][41][42], both of which have been linked to sleep homeostasis [20,43].…”

Section: Discussionmentioning

confidence: 99%

Sepsis-Induced Brain State Instability

Kala

Leemburg

Ježek

2022

Preprint

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Background Sepsis-associated brain dysfunction (SABD) is a frequent severe complication of sepsis and the systemic inflammatory response syndrome. It is associated with high mortality and a majority of survivors suffer long-term neurological consequences. Sleep is commonly affected in sepsis and there is a strong correlation between its impairment and development of other complications or increased mortality in sepsis patients. Here, we investigate the effects of sepsis on brain activity patterns in order to better understand possible sources of sleep-wake disturbances associated with severe systemic inflammation. Methods We studied the effects of high LPS doses (10mg/kg) on oscillatory brain states in an acute rat model of sepsis under urethane anaesthesia, which maintains REM- and NREM sleep-like states. Twelve Long-Evans rats (6 LPS, 6 controls) were implanted with eight independently movable tetrodes in the dorsal hippocampus. Baseline LFP activity was recorded for 3 hours after saline injection, followed by another 3 hours after LPS or saline injection. REM and NREM were automatically classified based on LFP activity and quantified. Within- and between-state dynamics were analysed using a 2-D state space approach based on spectral power ratios. Aperiodic and periodic components of the power spectrum were quantified for each state. Blood serum samples and brains were collected for IL-1β quantification and histological verification of electrode placement. Results Soon after LPS injection we observed a robust fragmentation of both oscillatory states resulting in a three-fold increase in the number of state transitions that lasted for several hours, although the overall time spent in either state did not change. Analysis of power spectra showed opposing shifts in low frequency oscillations (1–9 Hz) in REM and NREM that resulted in increased similarity between both states in 2-D state space. Conclusions The observed increased spectral similarity between REM and NREM and increased instability within the states may point to a mechanism underlying the severe sleep fragmentation described both in sepsis patients and in SABD animal models.

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“…Additionally, modeling severity based on mortality outcomes –in line with increasing refinement measures over the last decades– is challenging in animal research, as euthanasia upon meeting the earliest possible humane endpoint criteria outweighs the study of other predictors of death. In a study evaluating the sickness behavior score (SBS) in a rat CLP model, the authors reported mortality in CLP nonsurvivors, which was associated with elevated levels of SBS, whereas the SBS in surviving animals returned to a mild level 29 . Similar results were observed in the present study, showing CLP nonsurviving mice in the highest severity levels and survivors in the moderate severity levels.…”

Section: Discussionmentioning

confidence: 99%

One score to rule them all: severity assessment in laboratory mice

Talbot

Struve

Wassermann

et al. 2020

Preprint

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18Animal welfare and the refinement of experimental procedures are fundamental aspects of 19 biomedical research. They provide the basis for robust experimental designs and reproducibility of 20 results. In many countries, the determination of welfare is a mandatory legal requirement and 21 implies the assessment of the degree of the severity that an animal experiences during an 22 experiment. However, for an effective severity assessment, an objective and exact 23 approach/system/strategy is needed. In light of these demands, we have developed the Relative 24 Severity Assessment (RELSA) score. 25 This comprehensive composite score was established on the basis of physiological and behavioral 26 data from a surgical mouse study. Body weight, the Mouse Grimace Scale score, burrowing behavior, 27 and the telemetry-derived parameters heart rate, heart rate variability, temperature, and general 28 activity were used to investigate the quality of indicating severity during postoperative recovery. The 29 RELSA scores not only revealed individual severity levels but also allowed a comparison of severity in 30 distinct mouse models addressing colitis, sepsis, and restraint stress using a k-means clustering 31 approach with the maximum achieved RELSA scores. 32We discriminated and classified data from sepsis nonsurvivors into the highest relative severity level. 33Data from mice after intraperitoneal transmitter implantation and sepsis survivor al were located in 34 the next lower cluster, while data from mice subjected to colitis and restraint stress were placed in 35 the lowest severity cluster. Analysis of individual variables and their combinations revealed model-36and time-dependent contributions to severity levels. 37In conclusion, we propose the RELSA score as a validated tool for objective real-time applicability in 38 severity assessment and as a first step towards a unified and accessible risk assessment tool in 39 biomedical research. As an effective severity assessment system, it will fundamentally improve 40 animal welfare, as well as data quality and reproducibility. 41Laboratory Animals 3 or the European Directive on the protection of animals used for scientific 48 purposes 4 . Animal welfare describes a status of high quality of life, which relies on the consideration 49 and promotion of things to achieve good animal welfare 5,6 . Its assessment requires the monitoring of 50 animal affective states with both positive and negative valance 7 . The term severity assessment more 51 specifically addresses the categorization of negative affective states of animals under experimental 52 conditions; however, both the promotion of welfare and assessment of severity aim at the 53 recognition of any sign of suffering and thereby are essential for possible interventions to relieve the 54 burden during experiments and promote the refinement of procedures. Nevertheless, to achieve 55 compliance with scientific and regulatory requirements, an exact, evidence-based severity 56 assessment and the classification of severity ...

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Sickness Behavior Score Is Associated with Neuroinflammation and Late Behavioral Changes in Polymicrobial Sepsis Animal Model

Cited by 14 publications

References 64 publications

In utero exposure to morphine leads to sex-specific behavioral alterations that persist into adulthood in cross-fostered mice

In utero exposure to morphine leads to sex-specific behavioral alterations that persist into adulthood in cross-fostered mice

Sepsis-Induced Brain State Instability

One score to rule them all: severity assessment in laboratory mice

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