scholarly journals Transcriptome-(Phospho)proteome Characterization of the Brain of a Constitutional Model of Cytoplasmic-predominant Pten Expression With Autism-Like Phenotypes

2020 ◽  
Author(s):  
Stetson Thacker ◽  
Charis Eng
Keyword(s):  
Biological Networks ◽  
Autism Spectrum ◽  
Pten Expression ◽  
Differentially Expressed ◽  
Future Research ◽  
Wildtype Mouse ◽  
Network Analyses ◽  
Phosphorylated Proteins ◽  
Mass Spectrometry Technology ◽  
The Brain

Abstract BackgroundPTEN, a well-studied tumor suppressor, has one of the strongest Mendelian associations with autism spectrum disorder (ASD), representing a special case in autism’s complex genetic architecture. Animal modeling for constitutional Pten mutation creates an opportunity to study how disruption of Pten affects neurobiology, providing insights that may be generalizable or at least inform our understanding of ASD. Although the neural transcriptome has been well characterized in Pten models, little has been done concerning the proteome and phosphoproteome. This is a critical gap in knowledge given that these –omic landscapes are more proximal to the actively observed biology than the transcriptome.MethodsWe sought to comprehensively characterize the neural proteome and phosphoproteome of the Ptenm3m4/m3m4 mouse, which exhibits cytoplasmic-predominant Pten expression. Proteomic and phosphoproteomic scans of Ptenm3m4/m3m4 and wildtype mouse brain at two-weeks- (P14) and six-weeks-of-age (P40) were performed using liquid chromatography with tandem mass spectrometry technology. Following quantification of differentially expressed/phosphorylated proteins, we performed gene overlap, gene enrichment, pathway, and network analyses to identify the similarity across the various datasets and understand the affected biological landscape.ResultsWe identified numerous differentially expressed/phosphorylated proteins, finding that dysregulation was greater at P40, consistent with the prior neural transcriptome data. We found the affected biological pathways were largely related to PTEN function, neurological processes, or neuroinflammation. Although we found minimal overlap among differentially expressed transcriptome-proteome-phosphoproteome molecules between P14 and P40 brains, there was congruence amongst the affected pathways. Importantly, network analysis identified Pten and Psd-95 as predominant regulatory nodes in the proteome and phosphoproteome, respectively. Moreover, we found overlap between our differentially expressed/phosphorylated proteins and known ASD risk genes.ConclusionsDifferential expression/phosphorylation revealed by transcriptome-proteome/phosphoproteome analyses of a germline Pten mutation model point to ASD risk genes like Pten and Psd-95 as major hubs in the protein networks, highlighting their important regulatory influence. Our observations here suggest Pten and Psd-95, known interactors in biological networks in the brain, are critical to either initiation or maintenance of cellular and perhaps organismal phenotypes related to ASD. Future research should explore rescuing Pten and Psd-95 function in attempts to ameliorate neurological pathologies and behavioral abnormalities.

scholarly journals Transcriptome-(phospho)proteome characterization of brain of a germline model of cytoplasmic-predominant Pten expression with autism-like phenotypes

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Stetson Thacker ◽  
Charis Eng
Keyword(s):  
Autism Spectrum ◽  
Pten Expression ◽  
Differentially Expressed ◽  
Risk Genes ◽  
Animal Modeling ◽  
Network Analyses ◽  
Phosphorylated Proteins ◽  
Mass Spectrometry Technology ◽  
Neurological Processes

AbstractPTEN has a strong Mendelian association with autism spectrum disorder (ASD), representing a special case in autism’s complex genetic architecture. Animal modeling for constitutional Pten mutation creates an opportunity to study how disruption of Pten affects neurobiology and glean potential insight into ASD pathogenesis. Subsequently, we comprehensively characterized the neural (phospho)proteome of Ptenm3m4/m3m4 mice, which exhibits cytoplasmic-predominant Pten expression, by applying mass spectrometry technology to their brains at two-weeks- (P14) and six-weeks-of-age (P40). The differentially expressed/phosphorylated proteins were subjected to gene enrichment, pathway, and network analyses to assess the affected biology. We identified numerous differentially expressed/phosphorylated proteins, finding greater dysregulation at P40 consistent with prior transcriptomic data. The affected pathways were largely related to PTEN function or neurological processes, while scant direct overlap was found across datasets. Network analysis pointed to ASD risk genes like Pten and Psd-95 as major regulatory hubs, suggesting they likely contribute to initiation or maintenance of cellular and perhaps organismal phenotypes related to ASD.

scholarly journals BrainEXP-NPD: a database of transcriptomic profiles of human brains of six neuropsychiatric disorders

2021 ◽  
Author(s):  
Cuihua Xia ◽  
Teng Ma ◽  
Chuan Jiao ◽  
Chao Chen ◽  
Chunyu Liu
Keyword(s):  
Bipolar Disorder ◽  
Differential Expression ◽  
Differentially Expressed Genes ◽  
Neuropsychiatric Disorders ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Differentially Expressed ◽  
Sequencing Data ◽  
Network Analyses ◽  
Gene Differential Expression

Background: Spatio-temporal gene expression has been widely used to study gene functions and biological mechanisms in diseases. Numerous microarray and RNA sequencing data focusing on brain transcriptomes in neuropsychiatric disorders have accumulated. However, their consistency, reproducibility has not been properly evaluated. Except for a few psychiatric disorders, like schizophrenia, bipolar disorder and autism, most have not been compared to each other for cross-disorder comparisons. Methods: We organized 48 human brain transcriptome datasets from six sources. The original brain donors include patients with schizophrenia (SCZ, N=427), bipolar disorder (BD, N=312), major depressive disorder (MDD, N=219), autism spectrum disorder (ASD, N=53), Alzheimer's disease (AD, N=765), Parkinson's disease (PD, N=163) as well as controls as unaffected by such disorders (CTRL, N=6,378), making it a total of 8,317 samples. Raw data included multiple brain regions of both sexes, with ages ranging from embryonic to seniors. After standardization, quality control, filtering and removal of known and unknown covariates, we performed comprehensive meta- and mega- analyses, including gene differential expression and gene co-expression network. Results: A total of 6922, 3011, 2703, 4389, 3507, 4279 significantly differentially expressed genes (FDR q < 0.05) were detected in the comparisons of 6 brain regions of SCZ-CTRL, 5 brain regions of BD-CTRL, 6 brain regions of MDD-CTRL, 4 brain regions of ASD-CTRL, 7 brain regions of AD-CTRL, and 6 brain regions of PD-CTRL, respectively. Most differentially expressed genes were brain region-specific and disease-specific. SCZ and BD have a maximal transcriptome similarity in striatum (ρ=0.42) among the four brain regions, as measured by Spearman's correlation of differential expression log2 FC values. SCZ and MDD have a maximal transcriptome similarity in hippocampus (ρ=0.30) among the five brain regions. BD and MDD have a maximal transcriptome similarity in frontal cortex (ρ=0.45) among the five brain regions. Other disease pairs have a less transcriptome similarity (ρ<0.1) in all brain regions. PD is negatively correlated with SCZ, BD, and MDD in cerebellum and striatum. We also performed coexpression network analyses for different disorders and controls separately. We developed a database named BrainEXP-NPD (http://brainexpnpd.org:8088/BrainEXPNPD/), to provide a user-friendly web interface for accessing the data, and analytical results of meta- and mega-analyses, including gene differential expression and gene co-expression networks between cases and controls on different brain regions, sexes and age groups. Discussion: BrainEXP-NPD compiled the largest collection of brain transcriptomic data of major neuropsychiatric disorders and presented lists of differentially expressed genes and coexpression modules in multiple brain regions of six major disorders.

scholarly journals Application of functional near-infrared spectroscopy in the healthcare industry: A review

2019 ◽  
Vol 12 (06) ◽  
pp. 1930012 ◽  
Author(s):  
Keum-Shik Hong ◽  
M. Atif Yaqub
Keyword(s):  
Infrared Spectroscopy ◽  
Near Infrared Spectroscopy ◽  
Depressive Disorders ◽  
Near Infrared ◽  
Brain Activity ◽  
Autism Spectrum ◽  
Future Research ◽  
Functional Near Infrared Spectroscopy ◽  
Brain Hemodynamics ◽  
The Brain

Functional near-infrared spectroscopy (fNIRS), a growing neuroimaging modality, has been utilized over the past few decades to understand the neuronal behavior in the brain. The technique has been used to assess the brain hemodynamics of impaired cohorts as well as able-bodied. Neuroimaging is a critical technique for patients with impaired cognitive or motor behaviors. The portable nature of the fNIRS system is suitable for frequent monitoring of the patients who exhibit impaired brain activity. This study comprehensively reviews brain-impaired patients: The studies involving patient populations and the diseases discussed in more than 10 works are included. Eleven diseases examined in this paper include autism spectrum disorder, attention-deficit hyperactivity disorder, epilepsy, depressive disorders, anxiety and panic disorder, schizophrenia, mild cognitive impairment, Alzheimer’s disease, Parkinson’s disease, stroke, and traumatic brain injury. For each disease, the tasks used for examination, fNIRS variables, and significant findings on the impairment are discussed. The channel configurations and the regions of interest are also outlined. Detecting the occurrence of symptoms at an earlier stage is vital for better rehabilitation and faster recovery. This paper illustrates the usability of fNIRS for early detection of impairment and the usefulness in monitoring the rehabilitation process. Finally, the limitations of the current fNIRS systems (i.e., nonexistence of a standard method and the lack of well-established features for classification) and future research directions are discussed. The authors hope that the findings in this paper would lead to advanced breakthrough discoveries in the fNIRS field in the future.

The Influence of Background Auditory Noise on P50 and N100 Suppression Elicited by the Paired-Click Paradigm

2020 ◽  
Vol 34 (3) ◽  
pp. 171-178
Author(s):  
Samantha Major ◽  
Kimberly Carpenter ◽  
Logan Beyer ◽  
Hannah Kwak ◽  
Geraldine Dawson ◽  
...  
Keyword(s):  
Sensory Gating ◽  
Autism Spectrum ◽  
Inhibitory Response ◽  
Future Research ◽  
Typically Developing ◽  
Optimal Outcomes ◽  
Hyperactivity Disorder ◽  
Auditory Sensory Gating ◽  
Auditory Noise ◽  
P50 Suppression

Abstract. Auditory sensory gating is commonly assessed using the Paired-Click Paradigm (PCP), an electroencephalography (EEG) task in which two identical sounds are presented sequentially and the brain’s inhibitory response to the second sound is measured. Many clinical populations demonstrate reduced P50 and/or N100 suppression. Testing sensory gating in children may help to identify individuals at risk for neurodevelopmental disorders earlier, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), which could lead to more optimal outcomes. Minimal research has been done with children because of the difficulty of performing lengthy EEG experiments with young children, requiring them to sit still for long periods of time. We designed a modified, potentially child-friendly version of the PCP and evaluated it in typically developing adults. The PCP was administered twice, once in a traditional silent room (silent movie condition) and once with an audible movie playing (audible movie condition) to minimize boredom and enhance behavioral compliance. We tested whether P50 and N100 suppression were influenced by the presence of the auditory background noise from the movie. N100 suppression was observed in both hemispheres in the silent movie condition and in the left hemisphere only during the audible movie condition, though suppression was attenuated in the audible movie condition. P50 suppression was not observed in either condition. N100 sensory gating was successfully elicited with an audible movie playing during the PCP, supporting the use of the modified task for future research in both children and adults.

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.

Possibility that the Onset of Autism Spectrum Disorder is Induced by Failure of the Glutamine-Glutamate Cycle

2020 ◽  
Vol 14 (2) ◽  
pp. 170-174
Author(s):  
Koichi Kawada ◽  
Nobuyuki Kuramoto ◽  
Seisuke Mimori
Keyword(s):  
Autism Spectrum Disorder ◽  
Endoplasmic Reticulum ◽  
Environmental Factors ◽  
Endoplasmic Reticulum Stress ◽  
Synapse Formation ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Neurodevelopmental Disease ◽  
Number Of Patients ◽  
The Brain

: Autism spectrum disorder (ASD) is a neurodevelopmental disease, and the number of patients has increased rapidly in recent years. The causes of ASD involve both genetic and environmental factors, but the details of causation have not yet been fully elucidated. Many reports have investigated genetic factors related to synapse formation, and alcohol and tobacco have been reported as environmental factors. This review focuses on endoplasmic reticulum stress and amino acid cycle abnormalities (particularly glutamine and glutamate) induced by many environmental factors. In the ASD model, since endoplasmic reticulum stress is high in the brain from before birth, it is clear that endoplasmic reticulum stress is involved in the development of ASD. On the other hand, one report states that excessive excitation of neurons is caused by the onset of ASD. The glutamine-glutamate cycle is performed between neurons and glial cells and controls the concentration of glutamate and GABA in the brain. These neurotransmitters are also known to control synapse formation and are important in constructing neural circuits. Theanine is a derivative of glutamine and a natural component of green tea. Theanine inhibits glutamine uptake in the glutamine-glutamate cycle via slc38a1 without affecting glutamate; therefore, we believe that theanine may prevent the onset of ASD by changing the balance of glutamine and glutamate in the brain.

Oppositional Defiant Disorder and Related Disruptive Behaviors in Autism Spectrum Disorder

2020 ◽  
pp. 136-158
Author(s):  
Connor M. Kerns ◽  
Chandler Puhy ◽  
Chelsea M. Day ◽  
Steven J. Berkowitz
Keyword(s):  
Autism Spectrum Disorder ◽  
Oppositional Defiant Disorder ◽  
Challenging Behaviors ◽  
Disruptive Behaviors ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Future Research ◽  
Oppositional Defiant ◽  
Assessment And Treatment ◽  
Defiant Behavior

The Diagnostic and Statistical Manual of Mental Disorders, fifth edition characterizes oppositional defiant disorder (ODD) as reflecting pervasive patterns of irritable mood, defiant behavior, and/or vindictiveness. Youth with autism spectrum disorder (ASD) exhibit high rates of disruptive behaviors commonly associated with ODD, such as noncompliance, irritability, temper tantrums, and mood dysregulation. This chapter reviews the presentation of ODD in individuals with ASD, including current prevalence estimates, proposed etiology, validated assessment methods, and emerging best practices designed to treat challenging behaviors. Although there is a robust literature describing assessment and treatment procedures for disruptive behaviors in individuals with ASD, conceptualizing these hallmark behaviors within the framework of ODD is relatively novel and not without controversy. Discussion thus includes challenges around the applicability of the diagnostic criteria in this population and future research directions that may provide clarity on this issue.

Synthesis

2020 ◽  
pp. 421-428
Author(s):  
Lauren Brookman-Frazee ◽  
Amy Drahota ◽  
Colby Chlebowski ◽  
Yael Koenig ◽  
Katherine Nguyen Williams ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Autism Spectrum ◽  
Future Research ◽  
Research Directions ◽  
Course Assessment ◽  
Academic Partnerships ◽  
Assessment And Treatment ◽  
Important Field ◽  
Future Research Directions ◽  
Psychiatric Conditions

Recent research and clinical attention devoted to co-occurring psychiatric conditions within autism spectrum disorder (ASD) has led to significant advances in the understanding of and ability to assess and treat co-occurring problems effectively. This chapter summarizes those advances while also highlighting the substantial gaps that remain in the understanding of co-occurring problems in people with ASD. The chapter provides recommendations for future research directions in the areas of etiology, developmental course, assessment, and treatment. It also offers suggestions for improving the representativeness of research participants and strengthening community–academic partnerships in this important field of study.

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

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.

025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A11-A12
Author(s):  
Carolyn Jones ◽  
Randall Olson ◽  
Alex Chau ◽  
Peyton Wickham ◽  
Ryan Leriche ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Early Life ◽  
Autism Spectrum ◽  
Prairie Vole ◽  
Sleep Disruption ◽  
Glutamatergic Synapses ◽  
The Brain ◽  
Orbital Shaker

Abstract Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643

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