scholarly journals Syngap1 Dynamically Regulates the Fine-Scale Reorganization of Cortical Circuits in Response to Sensory Experience

2020 ◽  
Author(s):  
Nerea Llamosas ◽  
Thomas Vaissiere ◽  
Camilo Rojas ◽  
Sheldon Michaelson ◽  
Courtney A. Miller ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Cortical Plasticity ◽  
Neurodevelopmental Disorder ◽  
Spike Timing ◽  
Sensory Cortex ◽  
Fine Scale ◽  
Cortical Circuits ◽  
Population Activity ◽  
Cellular Processes

AbstractExperience induces complex, neuron-specific changes in population activity within sensory cortex circuits. However, the mechanisms that enable neuron-specific changes within cortical populations remain unclear. To explore the idea that synapse strengthening is involved, we studied fine-scale cortical plasticity in Syngap1 mice, a neurodevelopmental disorder model useful for linking synapse biology to circuit functions. Repeated functional imaging of the same L2/3 somatosensory cortex neurons during single whisker experience revealed that Syngap1 selectively regulated the plasticity of a low-active, or “silent”, neuronal subpopulation. Syngap1 also regulated spike-timing-dependent synaptic potentiation and experience-mediated in vivo synapse bouton formation, but not synaptic depression or bouton elimination in L2/3. Adult re-expression of Syngap1 restored plasticity of “silent” neurons, demonstrating that this gene controls dynamic cellular processes required for population-specific changes to cortical circuits during experience. These findings suggest that abnormal experience-dependent redistribution of cortical population activity may contribute to the etiology of neurodevelopmental disorders.

scholarly journals Cortical entrainment of human hypoglossal motor unit activities

2012 ◽  
Vol 107 (1) ◽  
pp. 493-499 ◽  
Author(s):  
Christopher M. Laine ◽  
Laura A. Nickerson ◽  
E. Fiona Bailey
Keyword(s):  
Motor Unit ◽  
Primary Motor Cortex ◽  
Spike Timing ◽  
Emg Activity ◽  
Motor Nucleus ◽  
Frequency Range ◽  
Population Activity ◽  
Single Motor Unit ◽  
Cortical Entrainment

Output from the primary motor cortex contains oscillations that can have frequency-specific effects on the firing of motoneurons (MNs). Whereas much is known about the effects of oscillatory cortical drive on the output of spinal MN pools, considerably less is known about the effects on cranial motor nuclei, which govern speech/oromotor control. Here, we investigated cortical input to one such motor pool, the hypoglossal motor nucleus (HMN), which controls muscles of the tongue. We recorded intramuscular genioglossus electromyogram (EMG) and scalp EEG from healthy adult subjects performing a tongue protrusion task. Cortical entrainment of HMN population activity was assessed by measuring coherence between EEG and multiunit EMG activity. In addition, cortical entrainment of individual MN firing activity was assessed by measuring phase locking between single motor unit (SMU) action potentials and EEG oscillations. We found that cortical entrainment of multiunit activity was detectable within the 15- to 40-Hz frequency range but was inconsistent across recordings. By comparison, cortical entrainment of SMU spike timing was reliable within the same frequency range. Furthermore, this effect was found to be intermittent over time. Our study represents an important step in understanding corticomuscular synchronization in the context of human oromotor control and is the first study to document SMU entrainment by cortical oscillations in vivo.

scholarly journals Myelin contributes to microstructural growth in human sensory cortex during early infancy.

2021 ◽  
Author(s):  
Mona Rosenke ◽  
Vaidehi S Natu ◽  
Hua Wu ◽  
Francesca R Querdasi ◽  
Holly Kular ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Brain Function ◽  
Model System ◽  
Sensory Cortex ◽  
Expression Data ◽  
Tissue Microstructure ◽  
Visual Areas ◽  
Infant Brain ◽  
Physical Changes

The infant brain undergoes rapid physical changes after birth. However, how cortex develops remains unknown. Using in vivo biomarkers of tissue microstructure, we find that infants' sensory-motor cortices undergo profound microstructural growth during the first six months of life. Using visual cortex as a model system, we find hierarchical microstructural growth: higher-level visual areas have less mature tissue at birth than earlier visual areas but grow at faster rates. Comparison of postnatal to prenatal gene expression data suggests that myelination and synaptic processes are dominant contributors to postnatal development. These data suggest a rethinking of developmental hypotheses and highlight the significance of cortical myelination in the development of brain function. Our findings have important implications for diagnosis of neurodevelopmental disorders and delays affecting life-long outcomes.

scholarly journals Uncovering Network Architecture Using an Exact Statistical Input-Output Relation of a Neuron Model

2018 ◽  
Author(s):  
Safura Rashid Shomali ◽  
Majid Nili Ahmadabadi ◽  
Seyyed Nader Rasuli ◽  
Hideaki Shimazaki
Keyword(s):  
Network Architecture ◽  
Background Activity ◽  
Spike Timing ◽  
Input Output ◽  
Unified Framework ◽  
Population Activity ◽  
Visual Neurons ◽  
V1 Neurons ◽  
Integrate And Fire

SummaryAn appealing challenge in Neuroscience is to identify network architecture from neural activity. A key requirement is the knowledge of statistical input-output relation of single neurons in vivo. Using a recent exact solution of spike-timing for leaky integrate-and-fire neurons under noisy inputs balanced near threshold, we construct a unified framework that links synaptic inputs, spiking nonlinearity, and network architecture, with statistics of population activity. The framework predicts structured higher-order interactions of neurons receiving common inputs under different architectures: It unveils two network motifs behind sparse activity reported in visual neurons. Comparing model’s prediction with monkey’s V1 neurons, we found excitatory inputs to pairs explain the sparse activity characterized by negative triple-wise interactions, ruling out shared inhibition. While the model predicts variation in the structured activity according to local circuitries, we show strong negative interactions are in general a signature of excitatory inputs to neuron pairs, whenever background activity is sparse.

scholarly journals Changing the responses of cortical neurons from sub- to suprathreshold using single spikes in vivo

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Verena Pawlak ◽  
David S Greenberg ◽  
Henning Sprekeler ◽  
Wulfram Gerstner ◽  
Jason ND Kerr
Keyword(s):  
Cortical Neurons ◽  
Time Course ◽  
Visual Stimulation ◽  
Spike Timing ◽  
Sensory Cortex ◽  
Sensory Coding ◽  
Computational Simulations ◽  
Subthreshold Voltage ◽  
Stimulus Features

Action Potential (APs) patterns of sensory cortex neurons encode a variety of stimulus features, but how can a neuron change the feature to which it responds? Here, we show that in vivo a spike-timing-dependent plasticity (STDP) protocol—consisting of pairing a postsynaptic AP with visually driven presynaptic inputs—modifies a neurons' AP-response in a bidirectional way that depends on the relative AP-timing during pairing. Whereas postsynaptic APs repeatedly following presynaptic activation can convert subthreshold into suprathreshold responses, APs repeatedly preceding presynaptic activation reduce AP responses to visual stimulation. These changes were paralleled by restructuring of the neurons response to surround stimulus locations and membrane-potential time-course. Computational simulations could reproduce the observed subthreshold voltage changes only when presynaptic temporal jitter was included. Together this shows that STDP rules can modify output patterns of sensory neurons and the timing of single-APs plays a crucial role in sensory coding and plasticity.

scholarly journals Interferon-ɣ Exposure of Human iPSC-derived Neurons Alters Major Histocompatibility Complex I and Synapsin I Protein Expression

2021 ◽  
Author(s):  
Adam Pavelinek ◽  
Rugile Matuleviciute ◽  
Laura Sichlinger ◽  
Lucia Dutan Polit ◽  
Nikos Armeniakos ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neurodevelopmental Disorders ◽  
Synapse Formation ◽  
Neurodevelopmental Disorder ◽  
Synaptic Proteins ◽  
Synapsin I ◽  
Mrna Levels ◽  
Maternal Immune Activation ◽  
Increased Risk

Human epidemiological data links maternal immune activation during gestation with increased risk for neurodevelopmental disorders including schizophrenia. Animal models of maternal immune activation (MIA) provide causal evidence for this association and strongly suggest that inflammatory cytokines act is a critical link between maternal infection and aberrant offspring brain and behavior development. This includes evidence for reduced synapse formation, consistent with post-mortem and in vivo evidence of reduced synaptic density in schizophrenia. However, to what extent specific cytokines are necessary and sufficient for these effects remains unclear. Using a human cellular model, we recently demonstrated that acute exposure to interferon-ɣ (IFNɣ) recapitulates molecular and cellular phenotypes associated with neurodevelopmental disorders. Here, we extend this work to test whether IFNɣ affects synapse formation in an induced neuron model that generates forebrain glutamatergic neurons. Using immunocytochemistry and quantitative PCR, we demonstrate that acute IFNɣ exposure results in significantly increased MHCI expression at the mRNA and protein level. Furthermore, acute IFNɣ exposure decreases synapsin I protein in neurons but does not affect synaptic gene mRNA levels. Interestingly, complement component 4A (C4A) mRNA is also significantly increased following acute IFNɣ exposure. This study builds on our previous work by showing that IFNɣ-mediated disruption of relevant synaptic proteins can occur at early stages of synapse formation, potentially contributing to neurodevelopmental disorder phenotypes such as schizophrenia.

scholarly journals The N-terminal BRCT domain determines MCPH1 function in brain development and fertility

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Xiaoqian Liu ◽  
Nadine Schneble-Löhnert ◽  
Martina Kristofova ◽  
Xiaobing Qing ◽  
Jan Labisch ◽  
...  
Keyword(s):  
Brain Size ◽  
Neurodevelopmental Disorder ◽  
Gonad Development ◽  
Brct Domain ◽  
Primary Microcephaly ◽  
Cellular Processes ◽  
Damage Response ◽  
Almost All

AbstractMCPH1 is a causal gene for the neurodevelopmental disorder, human primary microcephaly (MCPH1, OMIM251200). Most pathogenic mutations are located in the N-terminal region of the gene, which encodes a BRCT domain, suggesting an important function of this domain in brain size determination. To investigate the specific function of the N-terminal BRCT domain in vivo, we generated a mouse model lacking the N’-BRCT domain of MCPH1 (referred as Mcph1-ΔBR1). These mutant mice are viable, but exhibit reduced brain size, with a thinner cortex due to a reduction of neuroprogenitor populations and premature neurogenic differentiation. Mcph1-ΔBR1 mice (both male and female) are infertile; however, almost all female mutants develop ovary tumours. Mcph1-ΔBR1 MEF cells exhibit a defect in DNA damage response and DNA repair, and show the premature chromosome condensation (PCC) phenotype, a hallmark of MCPH1 patient cells and also Mcph1 knockout cells. In comparison with Mcph1 complete knockout mice, Mcph1-ΔBR1 mice faithfully reproduce all phenotypes, indicating an essential role of the N-terminal BRCT domain for the physiological function of MCPH1 in the control of brain size and gonad development as well as in multiple cellular processes.

scholarly journals Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ditte Olsen ◽  
Niels Wellner ◽  
Mathias Kaas ◽  
Inge E. M. de Jong ◽  
Florence Sotty ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Firing Pattern ◽  
Neurodevelopmental Disorder ◽  
Paradoxical Response ◽  
Dopaminergic Transmission ◽  
Hyperactivity Disorder ◽  
Responses To Dopamine ◽  
Circuit Function ◽  
Underlying Pathophysiology

AbstractAttention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2−/− mice uniquely recapitulate symptoms reminiscent of ADHD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2−/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2−/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.

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

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.

miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

2021 ◽  
pp. 1-12
Author(s):  
Pengli Wang ◽  
Dan Zheng ◽  
Hongyang Qi ◽  
Qi Gao
Keyword(s):  
Pancreatic Cancer ◽  
Hypoxia Inducible Factor ◽  
Immunofluorescence Assay ◽  
Luciferase Assay ◽  
Interacting Protein ◽  
Over Expression ◽  
Thioredoxin Interacting Protein ◽  
Cellular Processes ◽  
And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

scholarly journals The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

2020 ◽  
Author(s):  
Enrico Castroflorio ◽  
Joery den Hoed ◽  
Daria Svistunova ◽  
Mattéa J. Finelli ◽  
Alberto Cebrian-Serrano ◽  
...  
Keyword(s):  
Neurodevelopmental Disorders ◽  
Regulatory Protein ◽  
Molecular Function ◽  
Neuronal Connectivity ◽  
Nuclear Receptor Coactivator ◽  
Lysm Domain ◽  
Behavioural Assessment ◽  
And Function ◽  
The Brain

Abstract Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment. Graphic abstract

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