scholarly journals Effects of Chronic Administration of P-Cymene in an Animal Model of LPS-Induced Autism

2021 ◽  
Vol 8 (03) ◽  
pp. e104-e113
Author(s):  
Rick Wilhiam de Camargo ◽  
Marina Goulart da Silva ◽  
Guilherme Cabreira Daros ◽  
Fabiana Durante de Medeiros ◽  
Naiana da Rosa ◽  
...  
Keyword(s):  
Animal Model ◽  
Prenatal Exposure ◽  
Chronic Administration ◽  
Brain Structures ◽  
Autism Spectrum ◽  
Biochemical Tests ◽  
Behavioral Abnormalities ◽  
Stereotyped Movement ◽  
Behavioral Memory ◽  
Validation Tests

Abstract p-Cymene is a monoterpene found in over 100 plant species. It shows a range of biological activity, including anti-inflammatory and antimicrobial effects. It is possibly a new therapeutic alternative for autism spectrum disorder characterized by deficits in interaction and behavioral abnormalities. These symptoms can occur in response to maternal immune activation through prenatal exposure to lipopolysaccharide. Thus, this study aimed to evaluate the behavioral, memory, and biochemical effects of chronic administration of p-cymene in an animal model of autism by prenatal maternal exposure to lipopolysaccharide. Twenty-four pregnant Wistar rats were used, who received 100 μg/kg of lipopolysaccharide or saline intraperitoneally (i.p.) on the 9.5 gestational day. After birth, the male offspring remained with the mothers until weaning and underwent model validation tests on postnatal day 30. From postnatal day 31 on, chronic administration, via i.p., of saline (1 mL/kg), risperidone (0.2 mg/kg), or p-cymene (100 mg/kg) for 22 days was performed. The animals were submitted to behavioral (postnatal day 52) and memory tests (postnatal days 52–53) and subsequently sacrificed (postnatal day 54) when their brain structures were removed for quantification of proinflammatory cytokines (TNF-α, interleukin 1β, and interleukin 6). Prenatal exposure to lipopolysaccharide significantly increased episodes of stereotyped movement (p=0.0001) and decreased parameters of social interaction in offspring, including sniffing, following, mounting, and allowing mounting (p=0.0043, p<0.0001, p=0.0009, and p=0.0200, respectively). Chronic p-cymene treatment was not significant for behavioral, memory, and biochemical tests. However, due to their pharmacokinetic characteristics, p-cymene nanomaterials’ formulation may be an exciting alternative to be tested for further results.

scholarly journals When Genetic and Environmental Factors Meet in Modelling Autism

2021 ◽  
Author(s):  
◽  
Michaela Pettie
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Environmental Factors ◽  
Prenatal Exposure ◽  
Chronic Administration ◽  
Communication Delays ◽  
Pregnant Rats ◽  
Non Invasive ◽  
Administration Method ◽  
Interaction Approach

<p>Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterised by deficits in verbal and non-verbal communication, social interaction and repetitive behaviours (APA, 2013). The aetiology of ASD is mostly unknown, with continued research identifying a multitude of genetic and non-genetic factors. However, it is the interaction between environmental factors and the genetic background of an individual which leads to the development of ASD. There is an urgent need for improved animal models of ASD to further our understanding of the aetiology and particularly its pathophysiology, as this will aid in the development of much needed pharmaceutical treatments to alleviate the impact of adverse symptoms for individuals with ASD. Current animal models of ASD examine the genetic (e.g. serotonin transporter knock out rats) or the environmental (e.g. prenatal exposure to Valproate) contributions to the disorder, and very rarely a combination of the two.  This thesis aimed to improve the Valproate (VPA) induced ASD animal model with a genetic × environmental interaction approach, as well as optimising chronic administration of the VPA to pregnant rats. To this aim, a non-invasive method of delivering VPA was used, which allowed genetically normal rats to voluntarily consume VPA throughout pregnancy. The prenatal exposure to VPA led to ASD-like behaviours in the offspring (communication delays, increased social behaviour, and social aversion). Next, rats with a genetic deficit in SERT (SERT+/-) exposed to VPA throughout gestation, with an optimised administration method using gelatine pellets, which allowed for voluntary non-invasive consumption, and a more accurate administration of increased VPA doses. Overall, the chronic prenatal exposure to VPA in SERT+/- rats led to a mild ASD-like phenotype, with rats exhibiting communication delays, abnormal play behaviour, disrupted social preference, and to some extent increased anxiety-like behaviour. The brains of the adult offspring were examined for neuronal changes in the GABA interneurons in brain regions associated with social behaviour (amygdala and hippocampus). However, no significant effects of prenatal VPA exposure, genotype, or sex were found. Thus, the variations GABAergic system is unlikely to underlie the earlier identified behavioural alterations. Ultimately, this thesis has furthered the VPA induced ASD animal model with a genetic × environmental interaction approach, as well as optimising the chronic administration method for pregnant rats.</p>

scholarly journals When Genetic and Environmental Factors Meet in Modelling Autism

2021 ◽  
Author(s):  
◽  
Michaela Pettie
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Environmental Factors ◽  
Prenatal Exposure ◽  
Chronic Administration ◽  
Communication Delays ◽  
Pregnant Rats ◽  
Non Invasive ◽  
Administration Method ◽  
Interaction Approach

<p>Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterised by deficits in verbal and non-verbal communication, social interaction and repetitive behaviours (APA, 2013). The aetiology of ASD is mostly unknown, with continued research identifying a multitude of genetic and non-genetic factors. However, it is the interaction between environmental factors and the genetic background of an individual which leads to the development of ASD. There is an urgent need for improved animal models of ASD to further our understanding of the aetiology and particularly its pathophysiology, as this will aid in the development of much needed pharmaceutical treatments to alleviate the impact of adverse symptoms for individuals with ASD. Current animal models of ASD examine the genetic (e.g. serotonin transporter knock out rats) or the environmental (e.g. prenatal exposure to Valproate) contributions to the disorder, and very rarely a combination of the two.  This thesis aimed to improve the Valproate (VPA) induced ASD animal model with a genetic × environmental interaction approach, as well as optimising chronic administration of the VPA to pregnant rats. To this aim, a non-invasive method of delivering VPA was used, which allowed genetically normal rats to voluntarily consume VPA throughout pregnancy. The prenatal exposure to VPA led to ASD-like behaviours in the offspring (communication delays, increased social behaviour, and social aversion). Next, rats with a genetic deficit in SERT (SERT+/-) exposed to VPA throughout gestation, with an optimised administration method using gelatine pellets, which allowed for voluntary non-invasive consumption, and a more accurate administration of increased VPA doses. Overall, the chronic prenatal exposure to VPA in SERT+/- rats led to a mild ASD-like phenotype, with rats exhibiting communication delays, abnormal play behaviour, disrupted social preference, and to some extent increased anxiety-like behaviour. The brains of the adult offspring were examined for neuronal changes in the GABA interneurons in brain regions associated with social behaviour (amygdala and hippocampus). However, no significant effects of prenatal VPA exposure, genotype, or sex were found. Thus, the variations GABAergic system is unlikely to underlie the earlier identified behavioural alterations. Ultimately, this thesis has furthered the VPA induced ASD animal model with a genetic × environmental interaction approach, as well as optimising the chronic administration method for pregnant rats.</p>

scholarly journals The Effects of Maternal Interleukin-17A on Social Behavior, Cognitive Function, and Depression-Like Behavior in Mice with Altered Kynurenine Metabolites

2021 ◽  
Vol 14 ◽  
pp. 117864692110266
Author(s):  
Yuki Murakami ◽  
Yukio Imamura ◽  
Yoshiyuki Kasahara ◽  
Chihiro Yoshida ◽  
Yuta Momono ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
Maternal Serum ◽  
Fetal Plasma ◽  
Maternal Inflammation ◽  
Interleukin 17A ◽  
Behavioral Abnormalities ◽  
Neuroactive Compounds ◽  
The Impact

Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

scholarly journals Early Diagnostics and Early Intervention in Neurodevelopmental Disorders—Age-Dependent Challenges and Opportunities

2021 ◽  
Vol 10 (4) ◽  
pp. 861
Author(s):  
Mijna Hadders-Algra
Keyword(s):  
Early Intervention ◽  
High Risk ◽  
Early Detection ◽  
Developmental Disorders ◽  
Familial Risk ◽  
Brain Structures ◽  
Autism Spectrum ◽  
First Year ◽  
Early Diagnostics ◽  
Challenges And Opportunities

This review discusses early diagnostics and early intervention in developmental disorders in the light of brain development. The best instruments for early detection of cerebral palsy (CP) with or without intellectual disability are neonatal magnetic resonance imaging, general movements assessment at 2–4 months and from 2–4 months onwards, the Hammersmith Infant Neurological Examination and Standardized Infant NeuroDevelopmental Assessment. Early detection of autism spectrum disorders (ASD) is difficult; its first signs emerge at the end of the first year. Prediction with the Modified Checklist for Autism in Toddlers and Infant Toddler Checklist is possible to some extent and improves during the second year, especially in children at familial risk of ASD. Thus, prediction improves substantially when transient brain structures have been replaced by permanent circuitries. At around 3 months the cortical subplate has dissolved in primary motor and sensory cortices; around 12 months the cortical subplate in prefrontal and parieto-temporal cortices and cerebellar external granular layer have disappeared. This review stresses that families are pivotal in early intervention. It summarizes evidence on the effectiveness of early intervention in medically fragile neonates, infants at low to moderate risk, infants with or at high risk of CP and with or at high risk of ASD.

scholarly journals In Silico Exploration of the Potential Role of Acetaminophen and Pesticides in the Etiology of Autism Spectrum Disorder

Toxics ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 97
Author(s):  
Tristan Furnary ◽  
Rolando Garcia-Milian ◽  
Zeyan Liew ◽  
Shannon Whirledge ◽  
Vasilis Vasiliou
Keyword(s):  
Autism Spectrum Disorder ◽  
Prenatal Exposure ◽  
Pesticide Exposure ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Biomedical Literature ◽  
Spectrum Disorder ◽  
Biological Processes ◽  
Genetic Associations ◽  
Increased Risk

Recent epidemiological studies suggest that prenatal exposure to acetaminophen (APAP) is associated with increased risk of Autism Spectrum Disorder (ASD), a neurodevelopmental disorder affecting 1 in 59 children in the US. Maternal and prenatal exposure to pesticides from food and environmental sources have also been implicated to affect fetal neurodevelopment. However, the underlying mechanisms for ASD are so far unknown, likely with complex and multifactorial etiology. The aim of this study was to explore the potential effects of APAP and pesticide exposure on development with regards to the etiology of ASD by highlighting common genes and biological pathways. Genes associated with APAP, pesticides, and ASD through human research were retrieved from molecular and biomedical literature databases. The interaction network of overlapping genetic associations was subjected to network topology analysis and functional annotation of the resulting clusters. These genes were over-represented in pathways and biological processes (FDR p < 0.05) related to apoptosis, metabolism of reactive oxygen species (ROS), and carbohydrate metabolism. Since these three biological processes are frequently implicated in ASD, our findings support the hypothesis that cell death processes and specific metabolic pathways, both of which appear to be targeted by APAP and pesticide exposure, may be involved in the etiology of ASD. This novel exposures-gene-disease database mining might inspire future work on understanding the biological underpinnings of various ASD risk factors.

scholarly journals Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Freddy Zhang ◽  
Benjamin Rein ◽  
Ping Zhong ◽  
Treefa Shwani ◽  
Megan Conrow-Graham ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Social Preference ◽  
Intervention Strategy ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Male Mice ◽  
Behavioral Abnormalities ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

scholarly journals Nutritional Intervention with Dried Bonito Broth for the Amelioration of Aggressive Behaviors in Children with Prenatal Exposure to Dioxins in Vietnam: A Pilot Study

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1455
Author(s):  
Muneko Nishijo ◽  
Tai The Pham ◽  
Ngoc Thao Pham ◽  
Hai Thai Thu Duong ◽  
Ngoc Nghi Tran ◽  
...  
Keyword(s):  
Aggressive Behavior ◽  
Prenatal Exposure ◽  
Intervention Group ◽  
Experimental Period ◽  
Nutritional Intervention ◽  
Autism Spectrum ◽  
Aggressive Behaviors ◽  
Post Intervention ◽  
Dioxin Exposure ◽  
Covert Aggression

Dioxins have been suggested to induce inflammation in the intestine and brain and to induce neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), partly due to deficits in parvalbumin-positive neurons in the brain that are sensitive to inflammatory stress. Previously, we reported ADHD traits with increased aggressiveness in children with prenatal exposure to dioxins in Vietnam, whereas dried bonito broth (DBB) has been reported to suppress inflammation and inhibit aggressive behavior in animal and human studies. In the present study, we investigated the association between dioxin exposure and the prevalence of children with highly aggressive behaviors (Study 1), as well as the effects of DBB on the prevalence of children with highly aggressive behaviors (Study 2). Methods: In Study 1, we investigated the effects of dioxin exposure on the prevalence of children with high aggression scores, which were assessed using the Children’s Scale of Hostility and Aggression: Reactive/Proactive (C-SHARP) in dioxin-contaminated areas. The data were analyzed using a logistic regression model after adjusting for confounding factors. In Study 2, we performed nutritional intervention by administering DBB for 60 days to ameliorate the aggressiveness of children with high scores on the C-SHARP aggression scale. The effects of DBB were assessed by comparing the prevalence of children with high C-SHARP scores between the pre- and post-intervention examinations. Results: In Study 1, only the prevalence of children with high covert aggression was significantly increased with an increase in dioxin exposure. In Study 2, in the full ingestion (>80% of goal ingestion volume) group, the prevalence of children with high covert aggression associated with dioxin exposure was significantly lower in the post-ingestion examination compared with in the pre-ingestion examination. However, in other ingestion (<20% and 20–79%) groups and a reference (no intervention) group, no difference in the prevalence of children with high covert aggression was found between the examinations before and after the same experimental period. Conclusions: The findings suggest that DBB ingestion may ameliorate children’s aggressive behavior, which is associated with perinatal dioxin exposure.

scholarly journals Genetic Approaches Using Zebrafish to Study the Microbiota–Gut–Brain Axis in Neurological Disorders

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 566
Author(s):  
Jae-Geun Lee ◽  
Hyun-Ju Cho ◽  
Yun-Mi Jeong ◽  
Jeong-Soo Lee
Keyword(s):  
Neurological Disorders ◽  
Genetic Model ◽  
Molecular Genetic ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Bidirectional Signaling ◽  
Intestinal Dysbiosis ◽  
The Central Nervous System ◽  
The Brain

The microbiota–gut–brain axis (MGBA) is a bidirectional signaling pathway mediating the interaction of the microbiota, the intestine, and the central nervous system. While the MGBA plays a pivotal role in normal development and physiology of the nervous and gastrointestinal system of the host, its dysfunction has been strongly implicated in neurological disorders, where intestinal dysbiosis and derived metabolites cause barrier permeability defects and elicit local inflammation of the gastrointestinal tract, concomitant with increased pro-inflammatory cytokines, mobilization and infiltration of immune cells into the brain, and the dysregulated activation of the vagus nerve, culminating in neuroinflammation and neuronal dysfunction of the brain and behavioral abnormalities. In this topical review, we summarize recent findings in human and animal models regarding the roles of the MGBA in physiological and neuropathological conditions, and discuss the molecular, genetic, and neurobehavioral characteristics of zebrafish as an animal model to study the MGBA. The exploitation of zebrafish as an amenable genetic model combined with in vivo imaging capabilities and gnotobiotic approaches at the whole organism level may reveal novel mechanistic insights into microbiota–gut–brain interactions, especially in the context of neurological disorders such as autism spectrum disorder and Alzheimer’s disease.

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