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 Intraventricular IL-17A Administration Activates Microglia and Alters Their Localization in the Mouse Embryo Cerebral Cortex

2020 ◽  
Author(s):  
Tetsuya Sasaki ◽  
Saki Tome ◽  
Yosuke Takei
Keyword(s):  
Cerebral Cortex ◽  
Neural Progenitor Cells ◽  
Ventricular Zone ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
T Helper 17 ◽  
Maternal Immune Activation ◽  
Interleukin 17A ◽  
Cortical Dysgenesis ◽  
Behavioral Abnormalities

Abstract Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

scholarly journals Intraventricular IL-17A administration activates microglia and alters their localization in the mouse embryo cerebral cortex

2020 ◽  
Author(s):  
Tetsuya Sasaki ◽  
Saki Tome ◽  
Yosuke Takei
Keyword(s):  
Cerebral Cortex ◽  
Neural Progenitor Cells ◽  
Ventricular Zone ◽  
Fetal Brain ◽  
Autism Spectrum ◽  
T Helper 17 ◽  
Maternal Immune Activation ◽  
Interleukin 17A ◽  
Cortical Dysgenesis ◽  
Behavioral Abnormalities

Abstract Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

scholarly journals Melatonin as an Interventional Novel Candidate for the Individual with Autistic Fragile X Syndrome in Human

2017 ◽  
Author(s):  
Jinyoung Won ◽  
Yunho Jin ◽  
Tae Ho Lee ◽  
Sang-Rae Lee ◽  
Kyu-Tae Chang ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Fragile X ◽  
Neuroprotective Effect ◽  
Circadian Variation ◽  
Autism Spectrum ◽  
Behavioral Abnormalities ◽  
Metabolic Systems ◽  
The Impact

Fragile X syndrome (FXS) is the most frequent monogenic form of autism spectrum disorder (ASD). Autistic FXS is caused by loss of the fmr1 gene product, the fragile X mental retardation protein (FMRP), triggering physiological and behavioral abnormalities. It is correlated with clock components for behavioral circadian rhythm. Mutation of this gene causes the disturbances in sleep patterns and circadian behavior commonly observed in patients with autistic FXS, accompanied by frequent dysregulation of melatonin synthesis and melatonin-dependent signaling. These changes impair vigilance, learning and memory, and are also linked to autistic behavior including the abnormal anxiety response. However, although several possible causes, symptoms, and clinical features of ASD have been investigated, the correlation between an altered circadian rhythm and autistic FXS has not been extensively studied. Recent works have highlighted the impact of melatonin on the nervous, immune, and metabolic systems. Even though utilization of melatonin for sleep disorder in ASD has been considered in clinical research, further studies should be aimed at its neuroprotective role in ASD during developmental period. In this review, we focus on the regulatory circuits involved in melatonin dysregulation and circadian system disruption in those with autistic FXS. Additionally, we discuss the neuroprotective effect of melatonin intervention. This may improve neuroplasticity and physical capability. We also review the underlying molecular mechanisms, and suggest that melatonin may be a useful novel treatment for autistic FXS, countering the adverse effects of circadian variation.

scholarly journals Prenatal Stress and Maternal Immune Dysregulation in Autism Spectrum Disorders: Potential Points for Intervention

2020 ◽  
Vol 25 (41) ◽  
pp. 4331-4343 ◽  
Author(s):  
David Q. Beversdorf ◽  
Hanna E. Stevens ◽  
Kara Gross Margolis ◽  
Judy Van de Water
Keyword(s):  
Environmental Factors ◽  
Prenatal Stress ◽  
Maternal Stress ◽  
Significant Proportion ◽  
Fetal Brain ◽  
Immune Dysregulation ◽  
Autism Spectrum ◽  
Stress Exposure ◽  
Stress Susceptibility ◽  
The Impact

Background: Genetics is a major etiological contributor to autism spectrum disorder (ASD). Environmental factors, however, also appear to contribute. ASD pathophysiology due to gene x environment is also beginning to be explored. One reason to focus on environmental factors is that they may allow opportunities for intervention or prevention. Methods And Results: Herein, we review two such factors that have been associated with a significant proportion of ASD risk, prenatal stress exposure and maternal immune dysregulation. Maternal stress susceptibility appears to interact with prenatal stress exposure to affect offspring neurodevelopment. We also explore how maternal stress may interact with the microbiome in the neurodevelopmental setting. Additionally, understanding of the impact of maternal immune dysfunction on ASD has recently been advanced by recognition of specific fetal brain proteins targeted by maternal autoantibodies, and identification of unique mid-gestational maternal immune profiles. This might also be interrelated with maternal stress exposure. Animal models have been developed to explore pathophysiology targeting each of these factors. Conclusions: We are beginning to understand the behavioral, pharmacopathological, and epigenetic effects related to these interactions, and we are beginning to explore potential mitigating factors. Continued growth in understanding of these mechanisms may ultimately allow for the identification of multiple potential targets for prevention or intervention for this subset of environmental-associated ASD cases.

Aviation and the Microbiome

2020 ◽  
Vol 91 (8) ◽  
pp. 651-661
Author(s):  
Joshua T. Davis ◽  
Hilary A. Uyhelji
Keyword(s):  
Psychological Health ◽  
Aviation Safety ◽  
Autism Spectrum ◽  
Unintended Consequences ◽  
Microbial Colonization ◽  
Future Research ◽  
Aerospace Medicine ◽  
Medical Certification ◽  
Physical Disorders ◽  
The Impact

INTRODUCTION: Although the impact of microorganisms on their hosts has been investigated for decades, recent technological advances have permitted high-throughput studies of the collective microbial genomes colonizing a host or habitat, also known as the microbiome. This literature review presents an overview of microbiome research, with an emphasis on topics that have the potential for future applications to aviation safety. In humans, research is beginning to suggest relationships of the microbiome with physical disorders, including type 1 and type 2 diabetes mellitus, cardiovascular disease, and respiratory disease. The microbiome also has been associated with psychological health, including depression, anxiety, and the social complications that arise in autism spectrum disorders. Pharmaceuticals can alter microbiome diversity, and may lead to unintended consequences both short and long-term. As research strengthens understanding of the connections between the microbiota and human health, several potential applications for aerospace medicine and aviation safety emerge. For example, information derived from tests of the microbiota has potential future relevance for medical certification of pilots, accident investigation, and evaluation of fitness for duty in aerospace operations. Moreover, air travel may impact the microbiome of passengers and crew, including potential impacts on the spread of disease nationally and internationally. Construction, maintenance, and cleaning regimens that consider the potential for microbial colonization in airports and cabin environments may promote the health of travelers. Altogether, the mounting knowledge of microbiome effects on health presents several opportunities for future research into how and whether microbiome-based insights could be used to improve aviation safety.Davis JT, Uyhelji HA. Aviation and the microbiome. Aerosp Med Hum Perform. 2020; 91(8):651–661.

scholarly journals Effectiveness of Equine-Assisted Activities and Therapies for Improving Adaptive Behavior and Motor Function in Autism Spectrum Disorder

2021 ◽  
Vol 10 (8) ◽  
pp. 1726
Author(s):  
Leonardo Zoccante ◽  
Michele Marconi ◽  
Marco Luigi Ciceri ◽  
Silvia Gagliardoni ◽  
Luigi Alberto Gozzi ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Motor Function ◽  
Adaptive Behavior ◽  
Preliminary Evidence ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Parental Distress ◽  
Effective Option ◽  
The Impact ◽  
Equine Assisted

Equine-assisted activities and therapies (EAAT) have been suggested to improve adaptive behavior, and possibly motor function, in autism spectrum disorder (ASD). This study investigated the effects of EAAT on adaptive behavior and motor function in 15 children with ASD (13 males) aged 7–15 years as well as the impact of EAAT on the magnitude of stress in the parent–child system and the evolution in the child interaction with both the trained therapist and the therapeutic animal through the 20 weekly sessions of EAAT. EAAT were associated with greater adaptive behavior and coordination (all p ≤ 0.01) as well as a progressive improvement in the child’s abilities to respond to the increasing complexity of such form of positive behavioral support (all p < 0.001). However, EAAT did not prove to be effective in reducing parental distress. Collectively, preliminary evidence presented here may have important public health implications and gives reason to hope that EAAT could possibly be an effective option in ASD, warranting further investigation of its potential benefits in clinical trials among larger samples.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

Supporting Youth With Autism Learning Social Competence: A Comparison of Game- and Nongame-Based Activities in 3D Virtual World

2021 ◽  
pp. 073563312110220
Author(s):  
Xianhui Wang ◽  
Wanli Xing
Keyword(s):  
Social Interaction ◽  
Social Competence ◽  
Central Element ◽  
Autism Spectrum ◽  
Virtual Learning Environment ◽  
Learning Activities ◽  
Behavior Patterns ◽  
Interaction Behavior ◽  
Significant Difference ◽  
The Impact

This study explored youth with Autism Spectrum Disorder (ASD) learning social competence in the context of innovative 3D virtual learning environment and the effects of gaming as a central element of the learning experience. The empirical study retrospectively compared the social interactions of 11 adolescents with ASD in game-and nongame-based 3D collaborative learning activities in the same social competence training curriculum. We employed a learning analytics approach - association rule mining to uncover the associative rules of verbal social interaction and nonverbal social interaction contributors from the large dataset of the coded social behaviors. By comparing the rules across the game and nongame activities, we found a significant difference in youth with ASD’s social performance. The results of the group comparison study indicated that the co-occurrence of verbal and nonverbal behaviors is much stronger in the game-based learning activities. The game activities also yielded more diverse social interaction behavior patterns. On the other hand, in the nongame activities, students’ social interaction behavior patterns are much more limited. Furthermore, the impact of game design principles on learning is then discussed in this paper.

Smo-Shh signaling activator purmorphamine ameliorates neurobehavioral, molecular, and morphological alterations in an intracerebroventricular propionic acid-induced experimental model of autism

2021 ◽  
pp. 096032712110134
Author(s):  
S Rahi ◽  
R Gupta ◽  
A Sharma ◽  
S Mehan
Keyword(s):  
Propionic Acid ◽  
Developmental Process ◽  
Morphological Changes ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Autism Spectrum ◽  
Neurodevelopmental Disease ◽  
Shh Pathway ◽  
Apoptotic Markers ◽  
The Impact

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disease characterized by cognitive and sensorimotor impairment. Numerous research findings have consistently shown that alteration of Smo-Shh (smoothened-sonic hedgehog) signaling during the developmental process plays a significant role in ASD and triggers neuronal changes by promoting neuroinflammation and apoptotic markers. Purmorphamine (PUR), a small purine-derived agonist of the Smo-Shh pathway, shows resistance to hippocampal neuronal cell oxidation and decreases neuronal cell death. The goal of this study was to investigate the neuroprotective potential of PUR in brain intoxication induced by intracerebroventricular-propionic acid (ICV-PPA) in rats, with a focus on its effect on Smo-Shh regulation in the brain of rats. In addition, we analyze the impact of PUR on myelin basic protein (MBP) and apoptotic markers such as Caspase-3, Bax (pro-apoptotic), and Bcl-2 (anti-apoptotic) in rat brain homogenates. Chronic ICV-PPA infusion was administered consecutively for 11 days to induce autism in rats. In order to investigate behavioral alterations, rats were tested for spatial learning in the Morris Water Maze (MWM), locomotive alterations using actophotometer, and beam crossing task, while Forced Swimming Test (FST) for depressive behavior. PUR treatment with 5 mg/kg and 10 mg/kg (i.p.) was administered from day 12 to 44. Besides cellular, molecular and neuroinflammatory analyses, neurotransmitter levels and oxidative markers have also been studied in brain homogenates. The results of this study have shown that PUR increases the level of Smo-Shh and restores the neurochemical levels, and potentially prevents morphological changes, including demyelination.

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