DLX5/6 GABAergic expression affects social vocalization: implications for human evolution

ABSTRACTDLX5 and DLX6 are two closely related transcription factors involved in brain development and in GABAergic differentiation. The DLX5/6 locus is regulated by FoxP2, a gene involved in language evolution and has been associated to neurodevelopmental disorders and mental retardation. Targeted inactivation of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in behavioural and metabolic phenotypes notably increasing lifespan by 33%.Here, we show that Dlx5/6VgatCre mice present an hyper-vocalization and hyper-socialization phenotype. While only 7% of control mice emitted more than 700 vocalizations/10min, 30% and 56% of heterozygous or homozygous Dlx5/6VgatCre mice emitted more than 700 and up to 1400 calls/10min with longer, uninterrupted, call sequences and a higher proportion of complex and modulated calls. Hyper-vocalizing animals were more sociable: the time they spent in dynamic interactions with an unknown visitor was more than doubled compared to low-vocalizing individuals.We then compared the DLX5/6 genomic regions from Neanderthal and modern humans to examine if DLX5/6 GABAergic expression could have been involved in human social evolution. We identify an introgressed Neanderthal haplotype (DLX5/6-N-Haplotype) present in 12.6% of European individuals that covers DLX5/6 coding and regulatory sequences. The DLX5/6-N-Haplotype is not significantly associated to Autism Spectrum Disorders (ASDs) but includes the binding site for GTF2I, a gene associated to Williams-Beuren syndrome, a neurodevelopmental disorder characterized by hyper-sociability and hyper-vocalization. Interestingly, the DLX5/6-N-Haplotype is significantly underrepresented in semi-supercentenarians (>105y of age), a well-established human model of healthy ageing and longevity, suggesting its potential involvement in the co-evolution of longevity, sociability and speech.

Download Full-text

Oscillations or Synchrony? Disruption of Neural Synchrony despite Enhanced Gamma Oscillations in a Model of Disrupted Perceptual Coherence

Journal of Cognitive Neuroscience ◽

10.1162/jocn_a_00863 ◽

2015 ◽

Vol 27 (12) ◽

pp. 2416-2426 ◽

Cited By ~ 6

Author(s):

João Castelhano ◽

Inês Bernardino ◽

José Rebola ◽

Eugenio Rodriguez ◽

Miguel Castelo-Branco

Keyword(s):

Brain Activity ◽

Neurodevelopmental Disorder ◽

Gamma Oscillations ◽

Autism Spectrum ◽

Human Model ◽

Central Coherence ◽

Oscillatory Activity ◽

Neural Synchrony ◽

Coherent Integration ◽

Holistic Perception

It has been hypothesized that neural synchrony underlies perceptual coherence. The hypothesis of loss of central perceptual coherence has been proposed to be at the origin of abnormal cognition in autism spectrum disorders and Williams syndrome, a neurodevelopmental disorder linked with autism, and a clearcut model for impaired central coherence. We took advantage of this model of impaired holistic processing to test the hypothesis that loss of neural synchrony plays a separable role in visual integration using EEG and a set of experimental tasks requiring coherent integration of local elements leading to 3-D face perception. A profound reorganization of brain activity was identified. Neural synchrony was reduced across stimulus conditions, and this was associated with increased amplitude modulation at 25–45 Hz. This combination of a dramatic loss of synchrony despite increased oscillatory activity is strong evidence that synchrony underlies central coherence. This is the first time, to our knowledge, that dissociation between amplitude and synchrony is reported in a human model of impaired perceptual coherence, suggesting that loss of phase coherence is more directly related to disruption of holistic perception.

Download Full-text

Homogeneous intrinsic neuronal excitability induces overfitting to sensory noise: A robot model of neurodevelopmental disorder

10.31234/osf.io/ah89z ◽

2020 ◽

Author(s):

Hayato Idei ◽

Shingo Murata ◽

Yuichi Yamashita ◽

Tetsuya Ogata

Keyword(s):

Neurodevelopmental Disorders ◽

Neuronal Excitability ◽

Neurodevelopmental Disorder ◽

Predictive Coding ◽

Mechanistic Explanation ◽

Autism Spectrum ◽

Dynamic Interactions ◽

Developmental Learning ◽

Processing Level ◽

Sensory Noise

Neurodevelopmental disorders, including autism spectrum disorder, have been intensively investigated at the neural, cognitive, and behavioral levels, but the accumulated knowledge remains fragmented. Here, we propose a mechanistic explanation that unifies the disparate observations via a hierarchical predictive coding and developmental learning framework, which is demonstrated in experiments using a neural network-controlled robot. The results show that, through the developmental learning process, homogeneous intrinsic neuronal excitability at the neural level induced via self-organization changes at the information-processing level, such as hyper sensory precision and overfitting to sensory noise. These changes led to inflexibility, reduced generalization, and motor clumsiness at the behavioral level. These findings might bridge various levels of understandings in autism spectrum and other neurodevelopmental disorders and provide insights into the disease processes underlying observed behaviors and brain activities in individual patients. This study shows the potential of neurorobotics frameworks for modeling how psychiatric disorders arise from dynamic interactions among the brain, body, and uncertain environments.

Download Full-text

New research frameworks in the study of chimpanzee and gorilla sociality and communication

10.32942/osf.io/d8j3r ◽

2019 ◽

Author(s):

Sam G. B. Roberts ◽

Anna Roberts

Keyword(s):

Social Evolution ◽

Social Complexity ◽

Brain Size ◽

Social Systems ◽

Strongly Correlated ◽

The Social ◽

Human Social Evolution ◽

Research Frameworks ◽

New Research ◽

Large Groups

Group size in primates is strongly correlated with brain size, but exactly what makes larger groups more ‘socially complex’ than smaller groups is still poorly understood. Chimpanzees (Pan troglodytes) and gorillas (Gorilla gorilla) are among our closest living relatives and are excellent model species to investigate patterns of sociality and social complexity in primates, and to inform models of human social evolution. The aim of this paper is to propose new research frameworks, particularly the use of social network analysis, to examine how social structure differs in small, medium and large groups of chimpanzees and gorillas, to explore what makes larger groups more socially complex than smaller groups. Given a fission-fusion system is likely to have characterised hominins, a comparison of the social complexity involved in fission-fusion and more stable social systems is likely to provide important new insights into human social evolution

Download Full-text

Specialized Diet Therapies: Exploration for Improving Behavior in Autism Spectrum Disorder (ASD)

Current Medicinal Chemistry ◽

10.2174/0929867327666200217101908 ◽

2020 ◽

Vol 27 (40) ◽

pp. 6771-6786

Author(s):

Geir Bjørklund ◽

Nagwa Abdel Meguid ◽

Maryam Dadar ◽

Lyudmila Pivina ◽

Joanna Kałużna-Czaplińska ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Neurodevelopmental Disorder ◽

Caloric Intake ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Nutritional Deficiencies ◽

Childhood And Adolescence ◽

Restricted Interests ◽

Balanced Diet ◽

The Individual

As a major neurodevelopmental disorder, Autism Spectrum Disorder (ASD) encompasses deficits in communication and repetitive and restricted interests or behaviors in childhood and adolescence. Its etiology may come from either a genetic, epigenetic, neurological, hormonal, or an environmental cause, generating pathways that often altogether play a synergistic role in the development of ASD pathogenesis. Furthermore, the metabolic origin of ASD should be important as well. A balanced diet consisting of the essential and special nutrients, alongside the recommended caloric intake, is highly recommended to promote growth and development that withstand the physiologic and behavioral challenges experienced by ASD children. In this review paper, we evaluated many studies that show a relationship between ASD and diet to develop a better understanding of the specific effects of the overall diet and the individual nutrients required for this population. This review will add a comprehensive update of knowledge in the field and shed light on the possible nutritional deficiencies, metabolic impairments (particularly in the gut microbiome), and malnutrition in individuals with ASD, which should be recognized in order to maintain the improved socio-behavioral habit and physical health.

Download Full-text

FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09358-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Reymundo Lozano ◽

Catherine Gbekie ◽

Paige M. Siper ◽

Shubhika Srivastava ◽

Jeffrey M. Saland ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Medical Assessment ◽

Forkhead Box ◽

Organ Systems ◽

Practice Parameters ◽

Assessment And Monitoring ◽

Multidisciplinary Group ◽

The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

Download Full-text

Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

Download Full-text

LSD1 enzyme inhibitor TAK-418 unlocks aberrant epigenetic machinery and improves autism symptoms in neurodevelopmental disorder models

Science Advances ◽

10.1126/sciadv.aba1187 ◽

2021 ◽

Vol 7 (11) ◽

pp. eaba1187

Author(s):

Rina Baba ◽

Satoru Matsuda ◽

Yuuichi Arakawa ◽

Ryuji Yamada ◽

Noriko Suzuki ◽

...

Keyword(s):

Gene Expression ◽

Enzyme Activity ◽

Neurodevelopmental Disorders ◽

Neurodevelopmental Disorder ◽

Specific Inhibitor ◽

Autism Spectrum ◽

Poly I:C ◽

Control Of Gene Expression ◽

Epigenetic Machinery ◽

The Brain

Persistent epigenetic dysregulation may underlie the pathophysiology of neurodevelopmental disorders, such as autism spectrum disorder (ASD). Here, we show that the inhibition of lysine-specific demethylase 1 (LSD1) enzyme activity normalizes aberrant epigenetic control of gene expression in neurodevelopmental disorders. Maternal exposure to valproate or poly I:C caused sustained dysregulation of gene expression in the brain and ASD-like social and cognitive deficits after birth in rodents. Unexpectedly, a specific inhibitor of LSD1 enzyme activity, 5-((1R,2R)-2-((cyclopropylmethyl)amino)cyclopropyl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-3-carboxamide hydrochloride (TAK-418), almost completely normalized the dysregulated gene expression in the brain and ameliorated some ASD-like behaviors in these models. The genes modulated by TAK-418 were almost completely different across the models and their ages. These results suggest that LSD1 enzyme activity may stabilize the aberrant epigenetic machinery in neurodevelopmental disorders, and the inhibition of LSD1 enzyme activity may be the master key to recover gene expression homeostasis. TAK-418 may benefit patients with neurodevelopmental disorders.

Download Full-text

UTMOST, a single and cross-tissue TWAS (Transcriptome Wide Association Study), reveals new ASD (Autism Spectrum Disorder) associated genes

Translational Psychiatry ◽

10.1038/s41398-021-01378-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cristina Rodriguez-Fontenla ◽

Angel Carracedo

Keyword(s):

In Silico ◽

Association Studies ◽

Meta Analysis ◽

Neurodevelopmental Disorder ◽

Gastrointestinal Symptoms ◽

Tissue Expression ◽

Autism Spectrum ◽

Biological Characterization ◽

Large Size ◽

Body Tissues

AbstractAutism spectrum disorders (ASD) is a complex neurodevelopmental disorder that may significantly impact on the affected individual’s life. Common variation (SNPs) could explain about 50% of ASD heritability. Despite this fact and the large size of the last GWAS meta-analysis, it is believed that hundreds of risk genes in ASD have yet to be discovered. New tools, such as TWAS (Transcriptome Wide Association Studies) which integrate tissue expression and genetic data, are a great approach to identify new ASD susceptibility genes. The main goal of this study is to use UTMOST with the publicly available summary statistics from the largest ASD GWAS meta-analysis as genetic input. In addition, an in silico biological characterization for the novel associated loci was performed. Our results have shown the association of 4 genes at the brain level (CIPC, PINX1, NKX2-2, and PTPRE) and have highlighted the association of NKX2-2, MANBA, ERI1, and MITF at the gastrointestinal level. The gastrointestinal associations are quite relevant given the well-established but unexplored relationship between ASD and gastrointestinal symptoms. Cross-tissue analysis has shown the association of NKX2-2 and BLK. UTMOST-associated genes together with their in silico biological characterization seems to point to different biological mechanisms underlying ASD etiology. Thus, it would not be restricted to brain tissue and it will involve the participation of other body tissues such as the gastrointestinal.

Download Full-text

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

Toxics ◽

10.3390/toxics9050097 ◽

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.

Download Full-text

Mealtime Behaviors and Food Preferences of Students with Autism Spectrum Disorder

Foods ◽

10.3390/foods10010049 ◽

2020 ◽

Vol 10 (1) ◽

pp. 49

Author(s):

Hae Jin Park ◽

Su Jin Choi ◽

Yuri Kim ◽

Mi Sook Cho ◽

Yu-Ri Kim ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Nutrition Education ◽

Neurodevelopmental Disorder ◽

Food Preferences ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Online Questionnaire ◽

Mealtime Behavior ◽

High Level

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a lack of social communication and restrictive, repetitive behaviors or interests. This study aimed to examine the mealtime behaviors and food preferences of students with ASD. An online questionnaire on mealtime behavior and food preferences of ASD students was conducted by caregivers including parents, and the average age of ASD students was 14.1 ± 6.1. The analysis of mealtime behavior resulted in classification into three clusters: cluster 1, the “low-level problematic mealtime behavior group”; cluster 2, the “mid-level problematic mealtime behavior group”; and cluster 3, the “high-level problematic mealtime behavior group”. Cluster 1 included older students than other clusters and their own specific dietary rituals. Meanwhile, cluster 3 included younger students than other clusters, high-level problematic mealtime behavior, and a low preference for food. In particular, there were significant differences in age and food preference for each subdivided ASD group according to their eating behaviors. Therefore, the content and method of nutrition education for ASD students’ needs a detailed approach according to the characteristics of each group.

Download Full-text