scholarly journals Chromatin Remodeler CHD8 in Autism and Brain Development

2021 ◽  
Vol 10 (2) ◽  
pp. 366
Author(s):  
Anke Hoffmann ◽  
Dietmar Spengler
Keyword(s):  
Animal Studies ◽  
Mental Disease ◽  
Transgenic Animal ◽  
Autism Spectrum ◽  
Homeostatic Plasticity ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Facial Dysmorphism ◽  
Transcriptional Level ◽  
Level Function

Chromodomain Helicase DNA-binding 8 (CHD8) is a high confidence risk factor for autism spectrum disorders (ASDs) and the genetic cause of a distinct neurodevelopmental syndrome with the core symptoms of autism, macrocephaly, and facial dysmorphism. The role of CHD8 is well-characterized at the structural, biochemical, and transcriptional level. By contrast, much less is understood regarding how mutations in CHD8 underpin altered brain function and mental disease. Studies on various model organisms have been proven critical to tackle this challenge. Here, we scrutinize recent advances in this field with a focus on phenotypes in transgenic animal models and highlight key findings on neurodevelopment, neuronal connectivity, neurotransmission, synaptic and homeostatic plasticity, and habituation. Against this backdrop, we further discuss how to improve future animal studies, both in terms of technical issues and with respect to the sex-specific effects of Chd8 mutations for neuronal and higher-systems level function. We also consider outstanding questions in the field including ‘humanized’ mice models, therapeutic interventions, and how the use of pluripotent stem cell-derived cerebral organoids might help to address differences in neurodevelopment trajectories between model organisms and humans.

scholarly journals The microbial metabolite p-Cresol induces autistic-like behaviors in mice by remodeling the gut microbiota

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Patricia Bermudez-Martin ◽  
Jérôme A. J. Becker ◽  
Nicolas Caramello ◽  
Sebastian P. Fernandez ◽  
Renan Costa-Campos ◽  
...  
Keyword(s):  
Social Behavior ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Autism Spectrum ◽  
Dopamine Neurons ◽  
Therapeutic Interventions ◽  
Microbiota Composition ◽  
Microbial Metabolite ◽  
Central Dopamine Neurons ◽  
Induced Changes

Abstract Background Autism spectrum disorders (ASD) are associated with dysregulation of the microbiota-gut-brain axis, changes in microbiota composition as well as in the fecal, serum, and urine levels of microbial metabolites. Yet a causal relationship between dysregulation of the microbiota-gut-brain axis and ASD remains to be demonstrated. Here, we hypothesized that the microbial metabolite p-Cresol, which is more abundant in ASD patients compared to neurotypical individuals, could induce ASD-like behavior in mice. Results Mice exposed to p-Cresol for 4 weeks in drinking water presented social behavior deficits, stereotypies, and perseverative behaviors, but no changes in anxiety, locomotion, or cognition. Abnormal social behavior induced by p-Cresol was associated with decreased activity of central dopamine neurons involved in the social reward circuit. Further, p-Cresol induced changes in microbiota composition and social behavior deficits could be transferred from p-Cresol-treated mice to control mice by fecal microbiota transplantation (FMT). We also showed that mice transplanted with the microbiota of p-Cresol-treated mice exhibited increased fecal p-Cresol excretion, compared to mice transplanted with the microbiota of control mice. In addition, we identified possible p-Cresol bacterial producers. Lastly, the microbiota of control mice rescued social interactions, dopamine neurons excitability, and fecal p-Cresol levels when transplanted to p-Cresol-treated mice. Conclusions The microbial metabolite p-Cresol induces selectively ASD core behavioral symptoms in mice. Social behavior deficits induced by p-Cresol are dependant on changes in microbiota composition. Our study paves the way for therapeutic interventions targeting the microbiota and p-Cresol production to treat patients with ASD.

scholarly journals Metabolic Reprogramming by Reduced Calorie Intake or Pharmacological Caloric Restriction Mimetics for Improved Cancer Immunotherapy

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1260
Author(s):  
Erwan Eriau ◽  
Juliette Paillet ◽  
Guido Kroemer ◽  
Jonathan G. Pol
Keyword(s):  
Clinical Trials ◽  
Caloric Restriction ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Metabolic Reprogramming ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Calorie Intake ◽  
Multiple Model ◽  
Autophagy Induction

Caloric restriction and fasting have been known for a long time for their health- and life-span promoting effects, with coherent observations in multiple model organisms as well as epidemiological and clinical studies. This holds particularly true for cancer. The health-promoting effects of caloric restriction and fasting are mediated at least partly through their cellular effects—chiefly autophagy induction—rather than reduced calorie intake per se. Interestingly, caloric restriction has a differential impact on cancer and healthy cells, due to the atypical metabolic profile of malignant tumors. Caloric restriction mimetics are non-toxic compounds able to mimic the biochemical and physiological effects of caloric restriction including autophagy induction. Caloric restriction and its mimetics induce autophagy to improve the efficacy of some cancer treatments that induce immunogenic cell death (ICD), a type of cellular demise that eventually elicits adaptive antitumor immunity. Caloric restriction and its mimetics also enhance the therapeutic efficacy of chemo-immunotherapies combining ICD-inducing agents with immune checkpoint inhibitors targeting PD-1. Collectively, preclinical data encourage the application of caloric restriction and its mimetics as an adjuvant to immunotherapies. This recommendation is subject to confirmation in additional experimental settings and in clinical trials. In this work, we review the preclinical and clinical evidence in favor of such therapeutic interventions before listing ongoing clinical trials that will shed some light on this subject.

scholarly journals Enhancing Recovery after Stroke with Noradrenergic Pharmacotherapy: A New Frontier?

2000 ◽  
Vol 27 (2) ◽  
pp. 97-105 ◽  
Author(s):  
David J. Gladstone ◽  
Sandra E. Black
Keyword(s):  
Animal Studies ◽  
Recovery Of Function ◽  
Recovery Process ◽  
Stroke Recovery ◽  
Therapeutic Interventions ◽  
New Frontier ◽  
Focal Brain Injury ◽  
Completed Stroke ◽  
Scientific Attention ◽  
Irreversible Injury

ABSTRACT:Despite much progress in stroke prevention and acute intervention, recovery and rehabilitation have traditionally received relatively little scientific attention. There is now increasing interest in the development of stroke recovery drugs and innovative rehabilitation techniques to promote functional recovery after completed stroke. Experimental work over the past two decades indicates that pharmacologic intervention to enhance recovery may be possible in the subacute stage, days to weeks poststroke, after irreversible injury has occurred. This paper discusses the concept of “rehabilitation pharmacology” and reviews the growing literature from animal studies and pilot clinical trials on noradrenergic pharmacotherapy, a new experimental strategy in stroke rehabilitation. Amphetamine, a monoamine agonist that increases brain norepinephrine levels, is the most extensively studied drug shown to promote recovery of function in animal models of focal brain injury. Further research is needed to investigate the mechanisms and clinical efficacy of amphetamine and other novel therapeutic interventions on the recovery process.

scholarly journals Multi-environment phenotyping of C. elegans for robust evaluation of physical performance

2020 ◽  
Author(s):  
Jennifer E. Hewitt ◽  
Ricardo Laranjeiro ◽  
Masoud Norouzi ◽  
Rebecca Ellwood ◽  
Adam Antebi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Physical Performance ◽  
Current Treatment ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
C Elegans ◽  
Drug Candidates ◽  
Treatment Standard ◽  
Drug Interventions

ABSTRACTDetermining the physical performance of humans using several measures is essential to evaluating the severity of diseases, understanding the role of environmental factors, and developing therapeutic interventions. Development of analogous measures of physical performance in model organisms can help in identifying conserved signaling pathways and prioritizing drug candidates. In this study, we propose a multi-environment phenotyping (MEP) approach that generates a comprehensive set of measures indicative of physical performance in C. elegans. We challenge C. elegans in different mechanical environments of burrowing, swimming, and crawling, each of which places different physiological demands on the animals to generate locomotory forces. Implementation of the MEP approach is done using three established assays corresponding to each environment–a hydrogel-based burrowing assay, the CeleST swim assay, and the NemaFlex crawling strength assay. Using this approach, we study individuals and show that these three assays report on unique aspects of nematode physiology, as phenotypic measures obtained from different environments do not correlate with one another. Analysis of a subset of genes representative of oxidative stress, glucose metabolism, and fat metabolism show differential expression depending on the animal’s environment, suggesting that each environment evokes a response with distinct genetic requirements. To demonstrate the utility of the MEP platform, we evaluate the response of a muscular dystrophy model of C. elegans dys-1 to drug interventions of prednisone, melatonin and serotonin. We find that prednisone, which is the current treatment standard for human Duchenne muscular dystrophy, confers benefits in all three assays. Furthermore, while the tested compounds improve the physical performance of dys-1, these compounds are not able to fully restore the measures to wild-type levels, suggesting the need for discovery efforts to identify more efficacious compounds that could be aided using the MEP platform. In summary, the MEP platform’s ability to robustly define C. elegans locomotory phenotypes demonstrates the utility of the MEP approach toward identification of candidates for therapeutic intervention, especially in disease models in which the neuromuscular performance is impaired.

scholarly journals The Effects of Intermittent Fasting on Brain and Cognitive Function

2021 ◽  
Author(s):  
Jip Gudden ◽  
Alejandro Arias Vasquez ◽  
Mirjam Bloemendaal
Keyword(s):  
Cognitive Function ◽  
Animal Studies ◽  
Randomized Clinical Trials ◽  
Caloric Intake ◽  
Autism Spectrum ◽  
Future Research ◽  
Intermittent Fasting ◽  
Long Term Effects ◽  
Functional Changes ◽  
Positive Effects

The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 hours, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischaemic stroke, autism spectrum disorder and mood- and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Also, variations in fasting patterns, total caloric intake and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and Randomized Clinical Trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.

scholarly journals Self-Directedness and Cooperativeness, Psychosocial Dysfunction and Suffering in ESSENCE

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Danilo Garcia ◽  
Henrik Anckarsäter ◽  
Sebastian Lundström
Keyword(s):  
Developmental Coordination Disorder ◽  
Population Level ◽  
Autism Spectrum ◽  
Severe Form ◽  
Therapeutic Interventions ◽  
Psychosocial Dysfunction ◽  
Hyperactivity Disorder ◽  
Character Inventory ◽  
Novel Method ◽  
The Impact

Background. The acronym ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) highlights that children seeking clinical treatment are often multiply impaired, thus requiring treatment from several specialties. The aim was to map and relate, on a population level, ESSENCE to two salient predictors of health and adaptation to adversities, namely, Self-Directedness and Cooperativeness and also to dysfunction and suffering.Methods. Participants were twins(N=1892)aged 9 or 12 whose parents were interviewed with the Autism-Tics, ADHD and other Comorbidities inventory (A-TAC), and the Junior Temperament and Character Inventory (J-TCI). The A-TAC was first used to discern four ESSENCE-related screening diagnoses: autism spectrum disorders, attention deficit hyperactivity disorder, learning disabilities, and developmental coordination disorder; second, to quantify dysfunction and suffering in important social areas.Results. ESSENCE symptoms were continuously and categorically associated with deficiency in Self-Directedness and Cooperativeness and higher ratings of dysfunction and suffering. The impact of ESSENCE symptoms on these measures of mental health was found in a milder form in about 16% of all children and in a severe form in about 2%.Conclusion. Therapeutic interventions focusing on Self-Directedness and Cooperativeness might provide a novel method for child psychiatry in its approach to ESSENCE.

scholarly journals Increased burden of deleterious variants in essential genes in autism spectrum disorder

2016 ◽  
Vol 113 (52) ◽  
pp. 15054-15059 ◽  
Author(s):  
Xiao Ji ◽  
Rachel L. Kember ◽  
Christopher D. Brown ◽  
Maja Bućan
Keyword(s):  
Autism Spectrum Disorder ◽  
Large Scale ◽  
De Novo ◽  
Autism Spectrum ◽  
Essential Genes ◽  
Spectrum Disorder ◽  
Model Organisms ◽  
Disease Genes ◽  
Priority List ◽  
Human Orthologs

Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication, and repetitive behavior. It is estimated that hundreds of genes contribute to ASD. We asked if genes with a strong effect on survival and fitness contribute to ASD risk. Human orthologs of genes with an essential role in pre- and postnatal development in the mouse [essential genes (EGs)] are enriched for disease genes and under strong purifying selection relative to human orthologs of mouse genes with a known nonlethal phenotype [nonessential genes (NEGs)]. This intolerance to deleterious mutations, commonly observed haploinsufficiency, and the importance of EGs in development suggest a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. With a comprehensive catalog of 3,915 mammalian EGs, we provide compelling evidence for a stronger contribution of EGs to ASD risk compared with NEGs. By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, we show a significantly higher burden of damaging mutations in EGs in ASD probands compared with their non-ASD siblings. The analysis of EGs in the developing brain identified clusters of coexpressed EGs implicated in ASD. Finally, we suggest a high-priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Overall, we show that large-scale studies of gene function in model organisms provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of human disease.

scholarly journals Fetal Valproate Syndrome – A Case Report

2018 ◽  
Vol 1 (1) ◽  
Keyword(s):  
Valproic Acid ◽  
Female Child ◽  
Autism Spectrum ◽  
Facial Dysmorphism ◽  
In Utero Exposure ◽  
Fetal Valproate Syndrome ◽  
Drug History ◽  
Case Characteristics ◽  
Convulsant Drug ◽  
In Pregnancy

Background: Fetal Valproate Syndrome (FVS) results from prenatal exposure to valproic acid (VPA). Case characteristics: A four year old female child presented with facial dysmorphism and features of autism spectrum disorder (ASD). She had in-utero exposure to valproic acid (VPA). Message: VPA to be avoided in pregnancy and in Dysmorphism or ASD children maternal anti- convulsant drug history must be taken.

Ultrafast four-dimensional imaging of cardiac mechanical wave propagation with sparse optoacoustic sensing

2021 ◽  
Vol 118 (45) ◽  
pp. e2103979118
Author(s):  
Çağla Özsoy ◽  
Ali Özbek ◽  
Michael Reiss ◽  
Xosé Luís Deán-Ben ◽  
Daniel Razansky
Keyword(s):  
Wave Propagation ◽  
Cardiac Arrhythmias ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Cardiac Mapping ◽  
Mechanical Wave ◽  
Heart Motion ◽  
Life Threatening ◽  
Phase Singularities ◽  
Small Model

Propagation of electromechanical waves in excitable heart muscles follows complex spatiotemporal patterns holding the key to understanding life-threatening arrhythmias and other cardiac conditions. Accurate volumetric mapping of cardiac wave propagation is currently hampered by fast heart motion, particularly in small model organisms. Here we demonstrate that ultrafast four-dimensional imaging of cardiac mechanical wave propagation in entire beating murine heart can be accomplished by sparse optoacoustic sensing with high contrast, ∼115-µm spatial and submillisecond temporal resolution. We extract accurate dispersion and phase velocity maps of the cardiac waves and reveal vortex-like patterns associated with mechanical phase singularities that occur during arrhythmic events induced via burst ventricular electric stimulation. The newly introduced cardiac mapping approach is a bold step toward deciphering the complex mechanisms underlying cardiac arrhythmias and enabling precise therapeutic interventions.

Avatars and Digital Technology Literacy Applied in Psychology

2019 ◽  
pp. 402-420
Author(s):  
Judy Joohye Lee ◽  
Laura Dryjanska
Keyword(s):  
Media Literacy ◽  
Digital Technology ◽  
Autism Spectrum ◽  
Therapeutic Interventions ◽  
Technology Literacy ◽  
Clinical Settings ◽  
Diverse Populations ◽  
Virtual Technology ◽  
Technological Advances ◽  
Clinical Methods

Technological advances have led to a variety of positive outcomes and benefits. This chapter aims to discuss the different kinds of therapeutic interventions, clinical methods, and approaches in the field of psychology that have resulted from the advance in digital and virtual technology. In particular, this chapter focuses on avatars and virtual technology as a component of media literacy. Additionally, the chapter explores, in detail, how avatars are used across various clinical settings with diverse populations such as individuals with autism spectrum disorder, individuals with schizophrenia, prison settings, and the criminal justice system. Furthermore, the chapter highlights the significant implications avatars have in regards to education. Lastly, controversies and challenges are discussed regarding the efficacy of digital technology within clinical settings (e.g., telepsychology).

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