scholarly journals Inhibitory interneurons mediate autism-associated behaviors via 4E-BP2

2019 ◽  
Vol 116 (36) ◽  
pp. 18060-18067 ◽  
Author(s):  
Shane Wiebe ◽  
Anmol Nagpal ◽  
Vinh T. Truong ◽  
Jeehyun Park ◽  
Agnieszka Skalecka ◽  
...  
Keyword(s):  
Social Interaction ◽  
Translational Control ◽  
Vocal Communication ◽  
Inhibitory Neurons ◽  
Translational Repressor ◽  
Behavioral Abnormalities ◽  
Synaptic Functions ◽  
Stereotyped Behaviors ◽  
Cell Type Specific ◽  
And Behavior

Translational control plays a key role in regulation of neuronal activity and behavior. Deletion of the translational repressor 4E-BP2 in mice alters excitatory and inhibitory synaptic functions, engendering autistic-like behaviors. The contribution of 4E-BP2-dependent translational control in excitatory and inhibitory neurons and astrocytic cells to these behaviors remains unknown. To investigate this, we generated cell-type-specific conditional 4E-BP2 knockout mice and tested them for the salient features of autism, including repetitive stereotyped behaviors (self-grooming and marble burying), sociability (3-chamber social and direct social interaction tests), and communication (ultrasonic vocalizations in pups). We found that deletion of 4E-BP2 in GABAergic inhibitory neurons, defined by Gad2, resulted in impairments in social interaction and vocal communication. In contrast, deletion of 4E-BP2 in forebrain glutamatergic excitatory neurons, defined by Camk2a, or in astrocytes, defined by Gfap, failed to cause autistic-like behavioral abnormalities. Taken together, we provide evidence for an inhibitory-cell-specific role of 4E-BP2 in engendering autism-related behaviors.

The Use of fNIRS for Unique Contributions to Social and Affective Neuroscience

2019 ◽  
Author(s):  
Shannon Burns ◽  
Matthew D. Lieberman
Keyword(s):  
Infrared Spectroscopy ◽  
Social Interaction ◽  
Near Infrared Spectroscopy ◽  
Near Infrared ◽  
Affective Neuroscience ◽  
Functional Near Infrared Spectroscopy ◽  
Psychological Experience ◽  
The World ◽  
And Behavior ◽  
Meaningful Interaction

Social and affective neuroscience studies the neurophysiological underpinnings of psychological experience and behavior as it relates to the world around us. Yet, most neuroimaging methods require the removal of participants from their rich environment and the restriction of meaningful interaction with stimuli. In this Tools of the Trade article, we explain functional near infrared spectroscopy (fNIRS) as a neuroimaging method that can address these concerns. First, we provide an overview of how fNIRS works and how it compares to other neuroimaging methods common in social and affective neuroscience. Next, we describe fNIRS research that highlights its usefulness to the field – when rich stimuli engagement or environment embedding is needed, studies of social interaction, and examples of how it can help the field become more diverse and generalizable across participant populations. Lastly, this article describes how to use fNIRS for neuroimaging research with points of advice that are particularly relevant to social and affective neuroscience studies.

Digital Pollution and Its Impact on the Family and Social Interactions

2021 ◽  
pp. 0192513X2098555
Author(s):  
Shiv Ratan Agrawal
Keyword(s):  
Social Interaction ◽  
Social Interactions ◽  
Critical Dimensions ◽  
Digital Devices ◽  
The Family ◽  
Negative Effect ◽  
Potential Negative Effect ◽  
Human Attitude ◽  
Impact On Family ◽  
And Behavior

The present study was an attempt to identify the most prevailing means of digital devices and its impact as digital pollution on family and social interactions. Despite the obvious benefits of digital devices, in recent years researchers have taken more concern about its potential negative effect on human attitude and behavior, which in turn affects our society. A total of 613 usable responses were collected from Bangalore, India of excessive users of digital devices, such as a smartphone, computer/laptop, and television. All statistical analyses were performed using SPSS 23.0, AMOS 23.0, and SmartPLS 3.0. The results indicated that as the use of smartphone and computer/laptop increases, levels of digital pollution also increase, which in turn significantly triggers unfavorable impact on family and social interactions. The study indicated that digital pollution appears as an important predictor, which significantly affects social interaction unfavorably. The present study explored the various critical dimensions within this domain and delineated gaps in our knowledge of digital pollution. It was found that smartphones are more responsible for digital pollution among all the identified digital devices, followed by computer/laptop.

scholarly journals Dendritic Transport and Localization of Protein Kinase Mζ mRNA

2004 ◽  
Vol 279 (50) ◽  
pp. 52613-52622 ◽  
Author(s):  
Ilham Aliagaevich Muslimov ◽  
Volker Nimmrich ◽  
Alejandro Ivan Hernandez ◽  
Andrew Tcherepanov ◽  
Todd Charlton Sacktor ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Translational Control ◽  
Untranslated Region ◽  
Functional Integration ◽  
Long Term Potentiation ◽  
Memory Storage ◽  
Reading Frame ◽  
Cis Acting ◽  
Translational Repressor ◽  
Protein Kinase Mζ

Protein kinase Mζ (PKMζ) is an atypical protein kinase C isoform that has been implicated in the protein synthesis-dependent maintenance of long term potentiation and memory storage in the brain. Synapse-associated kinases are uniquely positioned to promote enduring consolidation of structural and functional modifications at the synapse, provided that kinase mRNA is available on site for local input-specific translation. We now report that the mRNA encoding PKMζ is rapidly transported and specifically localized to synaptodendritic neuronal domains. Transport of PKMζ mRNA is specified by two cis-acting dendritic targeting elements (Mζ DTEs). Mζ DTE1, located at the interface of the 5′-untranslated region and the open reading frame, directs somato-dendritic export of the mRNA. Mζ DTE2, in contrast, is located in the 3′-untranslated region and is required for delivery of the mRNA to distal dendritic segments. Colocalization with translational repressor BC1 RNA in hippocampal dendrites suggests that PKMζ mRNA may be subject to translational control in local domains. Dendritic localization of PKMζ mRNA provides a molecular basis for the functional integration of synaptic signal transduction and translational control pathways.

4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle

2000 ◽  
Vol 279 (4) ◽  
pp. E715-E729 ◽  
Author(s):  
O. Jameel Shah ◽  
Joshua C. Anthony ◽  
Scot R. Kimball ◽  
Leonard S. Jefferson
Keyword(s):  
Translational Control ◽  
Mrna Translation ◽  
Cellular Protein ◽  
Initiation Factor ◽  
Translational Repressor ◽  
Initiation Factors ◽  
Initiation Phase ◽  
Eukaryotic Initiation Factor 4E ◽  
Integration Sites ◽  
A Site

Maintenance of cellular protein stores in skeletal muscle depends on a tightly regulated synthesis-degradation equilibrium that is conditionally modulated under an extensive range of physiological and pathophysiological circumstances. Recent studies have established the initiation phase of mRNA translation as a pivotal site of regulation for global rates of protein synthesis, as well as a site through which the synthesis of specific proteins is controlled. The protein synthetic pathway is exquisitely sensitive to the availability of hormones and nutrients and employs a comprehensive integrative strategy to interpret the information provided by hormonal and nutritional cues. The translational repressor, eukaryotic initiation factor 4E binding protein 1 (4E-BP1), and the 70-kDa ribosomal protein S6 kinase (S6K1) have emerged as important components of this strategy, and together they coordinate the behavior of both eukaryotic initiation factors and the ribosome. This review discusses the role of 4E-BP1 and S6K1 in translational control and outlines the mechanisms through which hormones and nutrients effect changes in mRNA translation through the influence of these translational effectors.

scholarly journals Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

2022 ◽  
Vol 15 ◽  
Author(s):  
Gloria S. Lee ◽  
Devon L. Graham ◽  
Brenda L. Noble ◽  
Taylor S. Trammell ◽  
Deirdre M. McCarthy ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Motor Coordination ◽  
Cellular Level ◽  
D2 Receptors ◽  
Dopamine D2 Receptors ◽  
Inhibitory Neurons ◽  
Specific Loss ◽  
Dopamine D2 ◽  
And Behavior ◽  
Circuit Formation

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

scholarly journals SENP1 in the retrosplenial agranular cortex regulates core autistic-like symptoms in mice

2021 ◽  
Author(s):  
Kan Yang ◽  
Yuhan Shi ◽  
Xiujuan Du ◽  
Yuefang Zhang ◽  
Shifang Shan ◽  
...  
Keyword(s):  
Social Interaction ◽  
De Novo ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Genetic Components ◽  
Truncating Mutation ◽  
Synaptic Functions ◽  
Core Symptoms

AbstractAutism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental disorder. While the core symptoms of ASD are defects of social interaction and repetitive behaviors, over 50% of ASD patients have comorbidity of intellectual disabilities (ID) or developmental delay (DD), raising the question whether there are genetic components and neural circuits specific for core symptoms of ASD. Here, by focusing on ASD patients who do not show compound ID or DD, we identified a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene, coding the small ubiquitin-like modifiers (SUMO) deconjugating enzyme, as a potentially new candidate gene for ASD. We found that Senp1 haploinsufficient mice exhibited core symptoms of autism such as deficits in social interaction and repetitive behaviors, but normal learning and memory ability. Moreover, we found that the inhibitory and excitatory synaptic functions were severely affected in the retrosplenial agranular (RSA) cortex of Senp1 haploinsufficient mice. Lack of Senp1 led to over SUMOylation and degradation of fragile X mental retardation protein (FMRP) proteins, which is coded by the FMR1 gene, also implicated in syndromic autism. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescued the defects of synaptic functions and core autistic-like symptoms of Senp1 haploinsufficient mice. Taken together, these results elucidate that disruption of the SENP1-FMRP regulatory axis in the RSA may cause core autistic symptoms, which further provide a candidate brain region for therapeutic intervene of ASD by neural modulation approaches.

scholarly journals Features Of Hippocampal Astrocytic Domains And Their Spatial Relation To Excitatory And Inhibitory Neurons

2020 ◽  
Author(s):  
Ron Refaeli ◽  
Adi Doron ◽  
Aviya Benmelech-Chovav ◽  
Maya Groysman ◽  
Tirzah Kreisel ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Pyramidal Neurons ◽  
Spatial Relation ◽  
Design Principles ◽  
Inhibitory Neurons ◽  
Computational Tools ◽  
Close Proximity ◽  
Somatostatin Neurons ◽  
And Behavior ◽  
Elaborate Structure

SUMMARYThe mounting evidence for the involvement of astrocytes in neuronal circuits function and behavior stands in stark contrast to the lack of detailed anatomical description of these cells and the neurons in their domains. To fill this void, we imaged >30,000 astrocytes in cleared hippocampi, and employed converging genetic, histological and computational tools to determine the elaborate structure, distribution and neuronal content of astrocytic domains. First, we characterized the spatial distribution of >19,000 astrocytes across CA1 lamina, and analyzed the detailed morphology of thousands of reconstructed domains. We then determined the excitatory content of CA1 astrocytes, averaging above 13 pyramidal neurons per domain and increasing towards CA1 midline. Finally, we discovered that somatostatin neurons are found in close proximity to astrocytes, compared to parvalbumin and VIP inhibitory neurons. This resource expands our understanding of fundamental hippocampal design principles, and provides the first quantitative foundation for neuron-astrocyte interactions in this region.

scholarly journals Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

2020 ◽  
Author(s):  
Jelena Scekic-Zahirovic ◽  
Inmaculada Sanjuan-Ruiz ◽  
Vanessa Kan ◽  
Salim Megat ◽  
Pierre De Rossi ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Rna Binding ◽  
Gene Mutations ◽  
Neuronal Loss ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Behavioral Alterations ◽  
Behavioral Abnormalities ◽  
Cytoplasmic Accumulation

AbstractGene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS, lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

scholarly journals Early adolescent Rai1 reactivation reverses transcriptional and social interaction deficits in a mouse model of Smith–Magenis syndrome

2018 ◽  
Vol 115 (42) ◽  
pp. 10744-10749 ◽  
Author(s):  
Wei-Hsiang Huang ◽  
David C. Wang ◽  
William E. Allen ◽  
Matthew Klope ◽  
Hailan Hu ◽  
...  
Keyword(s):  
Social Interaction ◽  
Mouse Model ◽  
Behavioral Problems ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Critical Window ◽  
Genetic Mouse Model ◽  
Expression Of Genes ◽  
Syndromic Autism ◽  
Level 3

Haploinsufficiency of Retinoic Acid Induced 1 (RAI1) causes Smith–Magenis syndrome (SMS), a syndromic autism spectrum disorder associated with craniofacial abnormalities, intellectual disability, and behavioral problems. There is currently no cure for SMS. Here, we generated a genetic mouse model to determine the reversibility of SMS-like neurobehavioral phenotypes in Rai1 heterozygous mice. We show that normalizing the Rai1 level 3–4 wk after birth corrected the expression of genes related to neural developmental pathways and fully reversed a social interaction deficit caused by Rai1 haploinsufficiency. In contrast, Rai1 reactivation 7–8 wk after birth was not beneficial. We also demonstrated that the correct Rai1 dose is required in both excitatory and inhibitory neurons for proper social interactions. Finally, we found that Rai1 heterozygous mice exhibited a reduction of dendritic spines in the medial prefrontal cortex (mPFC) and that optogenetic activation of mPFC neurons in adults improved the social interaction deficit of Rai1 heterozygous mice. Together, these results suggest the existence of a postnatal temporal window during which restoring Rai1 can improve the transcriptional and social behavioral deficits in a mouse model of SMS. It is possible that circuit-level interventions would be beneficial beyond this critical window.

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