scholarly journals Sex-specific stress-related behavioral phenotypes and central amygdala dysfunction in a mouse model of 16p11.2 microdeletion

2020 ◽  
Author(s):  
Jacqueline Giovanniello ◽  
Sandra Ahrens ◽  
Kai Yu ◽  
Bo Li
Keyword(s):  
Neural Circuit ◽  
Genetic Model ◽  
Physical Restraint ◽  
Treatment Strategies ◽  
Autism Spectrum ◽  
Genomic Region ◽  
Central Amygdala ◽  
Emotional Symptoms ◽  
Microdeletion Syndrome ◽  
Female Specific

AbstractSubstantial evidence indicates that a microdeletion on human chromosome 16p11.2 is linked to neurodevelopmental disorders including autism spectrum disorders (ASD). Carriers of this deletion show divergent symptoms besides the core features of ASD, such as anxiety and emotional symptoms. The neural mechanisms underlying these symptoms are poorly understood. Here we report mice heterozygous for a deletion allele of the genomic region corresponding to the human 16p11.2 microdeletion locus (i.e., the ‘16p11.2 del/+ mice’) have sex-specific anxiety-related behavioral and neural circuit changes. We found that female, but not male 16p11.2 del/+ mice showed enhanced fear generalization – a hallmark of anxiety disorders – after auditory fear conditioning, and displayed increased anxiety-like behaviors after physical restraint stress. Notably, such sex-specific behavioral changes were paralleled by an increase in activity in central amygdala neurons projecting to the globus pallidus in female, but not male 16p11.2 del/+ mice. Together, these results reveal female-specific anxiety phenotypes related to 16p11.2 microdeletion syndrome and a potential underlying neural circuit mechanism. Our study therefore identifies previously underappreciated sex-specific behavioral and neural changes in a genetic model of 16p11.2 microdeletion syndrome, and highlights the importance of investigating female-specific aspects of this syndrome for targeted treatment strategies.

scholarly journals Sex Differences in Functional Connectivity Between Resting State Brain Networks in Autism Spectrum Disorder

2021 ◽  
Author(s):  
Vânia Tavares ◽  
Luís Afonso Fernandes ◽  
Marília Antunes ◽  
Hugo Ferreira ◽  
Diana Prata
Keyword(s):  
Autism Spectrum Disorder ◽  
Sex Differences ◽  
Resting State ◽  
Brain Connectivity ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Control Networks ◽  
Highly Sensitive ◽  
Female Specific ◽  
Main Effects

AbstractFunctional brain connectivity (FBC) has previously been examined in autism spectrum disorder (ASD) between-resting-state networks (RSNs) using a highly sensitive and reproducible hypothesis-free approach. However, results have been inconsistent and sex differences have only recently been taken into consideration using this approach. We estimated main effects of diagnosis and sex and a diagnosis by sex interaction on between-RSNs FBC in 83 ASD (40 females/43 males) and 85 typically developing controls (TC; 43 females/42 males). We found increased connectivity between the default mode (DM) and (a) the executive control networks in ASD (vs. TC); (b) the cerebellum networks in males (vs. females); and (c) female-specific altered connectivity involving visual, language and basal ganglia (BG) networks in ASD—in suggestive compatibility with ASD cognitive and neuroscientific theories.

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.

scholarly journals Autism Spectrum Disorder from the Womb to Adulthood: Suggestions for a Paradigm Shift

2021 ◽  
Vol 11 (2) ◽  
pp. 70
Author(s):  
Cristina Panisi ◽  
Franca Rosa Guerini ◽  
Provvidenza Maria Abruzzo ◽  
Federico Balzola ◽  
Pier Mario Biava ◽  
...  
Keyword(s):  
Paradigm Shift ◽  
Genetic Model ◽  
Time Window ◽  
Wide Spectrum ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Theoretical Issue ◽  
Common Thread ◽  
Spectrum Disorders ◽  
Interdisciplinary Healthcare

The wide spectrum of unique needs and strengths of Autism Spectrum Disorders (ASD) is a challenge for the worldwide healthcare system. With the plethora of information from research, a common thread is required to conceptualize an exhaustive pathogenetic paradigm. The epidemiological and clinical findings in ASD cannot be explained by the traditional linear genetic model, hence the need to move towards a more fluid conception, integrating genetics, environment, and epigenetics as a whole. The embryo-fetal period and the first two years of life (the so-called ‘First 1000 Days’) are the crucial time window for neurodevelopment. In particular, the interplay and the vicious loop between immune activation, gut dysbiosis, and mitochondrial impairment/oxidative stress significantly affects neurodevelopment during pregnancy and undermines the health of ASD people throughout life. Consequently, the most effective intervention in ASD is expected by primary prevention aimed at pregnancy and at early control of the main effector molecular pathways. We will reason here on a comprehensive and exhaustive pathogenetic paradigm in ASD, viewed not just as a theoretical issue, but as a tool to provide suggestions for effective preventive strategies and personalized, dynamic (from womb to adulthood), systemic, and interdisciplinary healthcare approach.

scholarly journals Bridging physiological and perceptual views of autism by means of sampling-based Bayesian inference

2021 ◽  
pp. 1-27
Author(s):  
Rodrigo Echeveste ◽  
Enzo Ferrante ◽  
Diego H. Milone ◽  
Inés Samengo
Keyword(s):  
Autism Spectrum Disorder ◽  
Neural Circuit ◽  
Autism Spectrum ◽  
Physiological Level ◽  
Cortical Dynamics ◽  
Significant Challenge ◽  
Characteristic Features ◽  
Neural Variability ◽  
Two Sides ◽  
Different Levels

Abstract Theories for autism spectrum disorder (ASD) have been formulated at different levels: ranging from physiological observations to perceptual and behavioral descriptions. Understanding the physiological underpinnings of perceptual traits in ASD remains a significant challenge in the field. Here we show how a recurrent neural circuit model which was optimized to perform sampling-based inference and displays characteristic features of cortical dynamics can help bridge this gap. The model was able to establish a mechanistic link between two descriptive levels for ASD: a physiological level, in terms of inhibitory dysfunction, neural variability and oscillations, and a perceptual level, in terms of hypopriors in Bayesian computations. We took two parallel paths: inducing hypopriors in the probabilistic model, and an inhibitory dysfunction in the network model, which lead to consistent results in terms of the represented posteriors, providing support for the view that both descriptions might constitute two sides of the same coin.

scholarly journals A genetic locus for paranoia

2018 ◽  
Vol 14 (1) ◽  
pp. 20170694 ◽  
Author(s):  
Bernard Crespi ◽  
Silven Read ◽  
Iiro Salminen ◽  
Peter Hurd
Keyword(s):  
Genetic Model ◽  
Genetic Locus ◽  
Large Population ◽  
Autism Spectrum ◽  
Psychological Effects ◽  
Imprinted Genes ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Altered Expression ◽  
Schizophrenia Spectrum

The psychological effects of brain-expressed imprinted genes in humans are virtually unknown. Prader–Willi syndrome (PWS) is a neurogenetic condition mediated by genomic imprinting, which involves high rates of psychosis characterized by hallucinations and paranoia, as well as autism. Altered expression of two brain-expressed imprinted genes, MAGEL2 and NDN , mediates a suite of PWS-related phenotypes, including behaviour, in mice. We phenotyped a large population of typical individuals for schizophrenia-spectrum and autism-spectrum traits, and genotyped them for the single-nucleotide polymorphism rs850807, which is putatively functional and linked with MAGEL2 and NDN . Genetic variation in rs850807 was strongly and exclusively associated with the ideas of reference subscale of the schizophrenia spectrum, which is best typified as paranoia. These findings provide a single-locus genetic model for analysing the neurological and psychological bases of paranoid thinking, and implicate imprinted genes, and genomic conflicts, in human mentalistic thought.

scholarly journals Sibling Relationships, Personality Traits, Emotional, and Behavioral Difficulties in Autism Spectrum Disorders

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
C. Longobardi ◽  
L. E. Prino ◽  
F. G. M. Gastaldi ◽  
T. Jungert
Keyword(s):  
Autism Spectrum Disorder ◽  
Sibling Relationships ◽  
Autism Spectrum ◽  
Sibling Relationship ◽  
Spectrum Disorder ◽  
Behavioral Difficulties ◽  
Typically Developing ◽  
Emotional Symptoms ◽  
The Impact

This study focused on parents’ perceptions of the quality of sibling relationship and its association with some behavioral and emotional characteristics of the typically developing sibling. The participants were parents of children with autism spectrum disorder and typically developing siblings. The sample size was 43. The group comprised 14 fathers (32.6%) and 29 mothers (67.4%) aged 33–53 years (M=43.56; SD = 5.23). The parents completed measures of siblings’ emotional and behavioral difficulties, siblings’ personality, and sibling relationships and their impact on families and siblings. The results showed that behavioral difficulties such as emotional symptoms, conduct problems, hyperactivity/inattention, and peer relationship problems were significantly associated with negative sibling relationships—characterized by rivalry, aggression, avoidance, and teaching behavior toward the brother or sister with an autism spectrum disorder. The implications are that sibling-focused interventions should focus on improving negative sibling relationships to reduce the impact on the difficulties of the typical development of the sibling of both genders and shape the content and delivery framework accordingly. This can be done by providing skills and approaches for enhancing sibling relationships so both parties benefit.

scholarly journals Environmental and Genetic Factors in Autism Spectrum Disorders: Special Emphasis on Data from Arabian Studies

2019 ◽  
Vol 16 (4) ◽  
pp. 658 ◽  
Author(s):  
Noor Almandil ◽  
Deem Alkuroud ◽  
Sayed AbdulAzeez ◽  
Abdulla AlSulaiman ◽  
Abdelhamid Elaissari ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Genetic Factors ◽  
Treatment Strategies ◽  
Autism Spectrum ◽  
Pharmacological Treatments ◽  
Protein Protein Interactions ◽  
Improve Treatment ◽  
Comprehensive Survey ◽  
Patterns Of Behavior ◽  
Spectrum Disorders

One of the most common neurodevelopmental disorders worldwide is autism spectrum disorder (ASD), which is characterized by language delay, impaired communication interactions, and repetitive patterns of behavior caused by environmental and genetic factors. This review aims to provide a comprehensive survey of recently published literature on ASD and especially novel insights into excitatory synaptic transmission. Even though numerous genes have been discovered that play roles in ASD, a good understanding of the pathophysiologic process of ASD is still lacking. The protein–protein interactions between the products of NLGN, SHANK, and NRXN synaptic genes indicate that the dysfunction in synaptic plasticity could be one reason for the development of ASD. Designing more accurate diagnostic tests for the early diagnosis of ASD would improve treatment strategies and could enhance the appropriate monitoring of prognosis. This comprehensive review describes the psychotropic and antiepileptic drugs that are currently available as effective pharmacological treatments and provides in-depth knowledge on the concepts related to clinical, diagnostic, therapeutic, and genetic perspectives of ASD. An increase in the prevalence of ASD in Gulf Cooperation Council countries is also addressed in the review. Further, the review emphasizes the need for international networking and multidimensional studies to design novel and effective treatment strategies.

scholarly journals Ocular Findings in the 16p11.2 Microdeletion Syndrome: A Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-5
Author(s):  
Cybil S. Stingl ◽  
Colleen Jackson-Cook ◽  
Natario L. Couser
Keyword(s):  
Literature Review ◽  
Wide Spectrum ◽  
Autism Spectrum ◽  
Extensive Literature ◽  
Microdeletion Syndrome ◽  
Ocular Adnexa ◽  
Hyperactivity Disorder ◽  
Ophthalmic Manifestations ◽  
Oppositional Defiant ◽  
Defiant Behavior

The recurrent 16p11.2 microdeletion is characterized by developmental delays and a wide spectrum of congenital anomalies. It has been well reported that individuals with this ∼593-kb interstitial deletion have an increased susceptibility toward the autism spectrum disorder (ASD). Abnormalities of the eye and ocular adnexa are also commonly associated findings seen in individuals with the 16p11.2 microdeletion syndrome, although these ophthalmic manifestations have not been well characterized. We conducted an extensive literature review to highlight the eye features in patients with the 16p11.2 microdeletion syndrome and describe a 5-year-old boy with the syndrome. The boy initially presented with intellectual disability, speech delay, and defiant behavior; diagnoses of attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) were established. He had a Chiari malformation type 1. His ophthalmic features included strabismus, hyperopia, and ptosis, and a posterior embryotoxon was present bilaterally. From a systematic review of prior reported cases, the most common eye and ocular adnexa findings observed were downslanting palpebral fissures, deep-set eyes, ptosis, and hypertelorism.

scholarly journals Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution

2016 ◽  
Vol 113 (8) ◽  
pp. E978-E986 ◽  
Author(s):  
Tanya M. Pennell ◽  
Freek J. H. de Haas ◽  
Edward H. Morrow ◽  
G. Sander van Doorn
Keyword(s):  
Sexual Conflict ◽  
Genetic Model ◽  
Arms Races ◽  
Female Partners ◽  
Intralocus Sexual Conflict ◽  
Antagonistic Coevolution ◽  
Evolutionary Conflict ◽  
Quantitative Genetic Model ◽  
Female Specific ◽  
Evolutionary Consequences

Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with wide-ranging evolutionary consequences. However, theory suggests that the scope for perpetual coevolution is limited, if traits involved in IRSC are subject to pleiotropic constraints. Here, we consider a biologically plausible form of pleiotropy that has hitherto been ignored in treatments of IRSC and arrive at drastically different conclusions. Our analysis is based on a quantitative genetic model of sexual conflict, in which genes controlling IRSC traits have side effects in the other sex, due to incompletely sex-limited gene expression. As a result, the genes are exposed to intralocus sexual conflict (IASC), a tug-of-war between opposing male- and female-specific selection pressures. We find that the interaction between the two forms of sexual conflict has contrasting effects on antagonistic coevolution: Pleiotropic constraints stabilize the dynamics of arms races if the mating traits are close to evolutionary equilibrium but can prevent populations from ever reaching such a state. Instead, the sexes are drawn into a continuous cycle of arms races, causing the buildup of IASC, alternated by phases of IASC resolution that trigger the next arms race. These results encourage an integrative perspective on the biology of sexual conflict and generally caution against relying exclusively on equilibrium stability analysis.

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