scholarly journals Restoring Shank3 in the rostral brainstem of shank3ab−/− zebrafish autism models rescues sensory deficits

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Robert A. Kozol ◽  
David M. James ◽  
Ivan Varela ◽  
Sureni H. Sumathipala ◽  
Stephan Züchner ◽  
...  
Keyword(s):  
Sensory Processing ◽  
Sensorimotor Integration ◽  
Brain Regions ◽  
Wild Type ◽  
Sensory Stimuli ◽  
Sensory Deficits ◽  
Light Sensing ◽  
Sensory Responsiveness ◽  
Behavioral Adaptations ◽  
Reduced Activity

AbstractPeople with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly exhibit reduced responses to sensory stimuli; yet the changes in brain-wide activity that link these symptoms to mutations in the shank3 gene remain unknown. Here we quantify movement in response to sudden darkness in larvae of two shank3 zebrafish mutant models and show that both models exhibit dampened responses to this stimulus. Using brain-wide activity mapping, we find that shank3−/− light-sensing brain regions show normal levels of activity while sensorimotor integration and motor regions are less active. Specifically restoring Shank3 function in a sensorimotor nucleus of the rostral brainstem enables the shank3−/− model to respond like wild-type. In sum, we find that reduced sensory responsiveness in shank3−/− models is associated with reduced activity in sensory processing brain regions and can be rescued by restoring Shank3 function in the rostral brainstem. These studies highlight the importance of Shank3 function in the rostral brainstem for integrating sensory inputs to generate behavioral adaptations to changing sensory stimuli.

scholarly journals Restoring Shank3 in a rostral sensorimotor brainstem nucleus rescues reduced light-evoked behaviors in shank3ab-/- zebrafish.

2021 ◽  
Author(s):  
Robert Kozol ◽  
David James ◽  
Ivan Varela ◽  
Sureni Sumathipala ◽  
Stephan Züchner ◽  
...  
Keyword(s):  
Sensorimotor Integration ◽  
Brain Activity ◽  
Visual Stimuli ◽  
Brain Nuclei ◽  
Sensory Responsiveness ◽  
Brain Circuits ◽  
Brainstem Nucleus ◽  
Reduced Light ◽  
The Brain ◽  
Reduced Activity

Abstract People with Phelan-McDermid Syndrome, caused by mutations in the SHANK3 gene, commonly present with symptoms of sensory hyporeactivity. To investigate how shank3 mutations impact brain circuits and contribute to sensory hyporeactivity, we generated two shank3 zebrafish mutant models. These shank3 mutant models both exhibit hyporeactivity to visual stimuli. Using whole-brain activity mapping, we show that light receptive brain nuclei show normal levels of activity while sensorimotor integration and motor regions are less active in shank3-/- mutants. Specifically rescuing Shank3 in a sensorimotor nucleus of the rostral brainstem is sufficient to rescue shank3-/- mutant hyporeactivity. In summary, reduced sensory responsiveness in shank3-/- mutant is associated with reduced activity across the brain and can be rescued by restoring Shank3 function in the rostral brainstem.

scholarly journals Implication of the Sensory Environment in Children with Autism Spectrum Disorder: Perspectives from School

2021 ◽  
Vol 18 (14) ◽  
pp. 7670
Author(s):  
Ana Gentil-Gutiérrez ◽  
José Luis Cuesta-Gómez ◽  
Paula Rodríguez-Fernández ◽  
Jerónimo Javier González-Bernal
Keyword(s):  
Autism Spectrum Disorder ◽  
Sensory Processing ◽  
Children With Autism ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Sensory Profile ◽  
School Factors ◽  
Cross Sectional ◽  
Sensory Stimuli ◽  
Children With Asd

(1) Background: Children with Autism Spectrum Disorder (ASD) frequently have difficulties in processing sensory information, which is a limitation when participating in different contexts, such as school. The objective of the present study was to compare the sensory processing characteristics of children with ASD in the natural context of school through the perception of professionals in the field of education, in comparison with neurodevelopmental children (2) Methods: A cross-sectional descriptive study as conducted with study population consisting of children between three and ten years old, 36 of whom were diagnosed with ASD and attended the Autismo Burgos association; the remaining 24 had neurotypical development. The degree of response of the children to sensory stimuli at school was evaluated using the Sensory Profile-2 (SP-2) questionnaire in its school version, answered by the teachers. (3) Results: Statistically significant differences were found in sensory processing patterns (p = 0.001), in sensory systems (p = 0.001) and in school factors (p = 0.001). Children with ASD who obtained worse results. (4) Conclusions: Children with ASD are prone to present sensory alterations in different contexts, giving nonadapted behavioral and learning responses.

scholarly journals Novel FGFR1 Variants Are Associated with Congenital Scoliosis

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1126
Author(s):  
Shengru Wang ◽  
Xiran Chai ◽  
Zihui Yan ◽  
Sen Zhao ◽  
Yang Yang ◽  
...  
Keyword(s):  
Protein Function ◽  
Hypogonadotropic Hypogonadism ◽  
Congenital Scoliosis ◽  
Wild Type ◽  
Conservation Analysis ◽  
Gene Assay ◽  
Protein Expressions ◽  
Patient Series ◽  
Reduced Activity

FGFR1 encodes a transmembrane cytokine receptor, which is involved in the early development of the human embryo and plays an important role in gastrulation, organ specification and patterning of various tissues. Pathogenic FGFR1 variants have been associated with Kallmann syndrome and hypogonadotropic hypogonadism. In our congenital scoliosis (CS) patient series of 424 sporadic CS patients under the framework of the Deciphering disorders Involving Scoliosis and COmorbidities (DISCO) study, we identified four unrelated patients harboring FGFR1 variants, including one frameshift and three missense variants. These variants were predicted to be deleterious by in silico prediction and conservation analysis. Signaling activities and expression levels of the mutated protein were evaluated in vitro and compared to that of the wild type (WT) FGFR1. As a result, the overall protein expressions of c.2334dupC, c.2339T>C and c.1261A>G were reduced to 43.9%, 63.4% and 77.4%, respectively. By the reporter gene assay, we observed significantly reduced activity for c.2334dupC, c.2339T>C and c.1261A>G, indicating the diminished FGFR1 signaling pathway. In conclusion, FGFR1 variants identified in our patients led to only mild disruption to protein function, caused milder skeletal and cardiac phenotypes than those reported previously.

scholarly journals The Role of Arg13 in Protein Phosphatase M tPphA from Thermosynechococcus elongatus

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jiyong Su ◽  
Karl Forchhammer
Keyword(s):  
Amino Acid ◽  
Protein Phosphatase ◽  
Arginine Residue ◽  
Side Chain ◽  
Wild Type ◽  
Catalytic Center ◽  
Nitrophenyl Phosphate ◽  
Reduced Activity ◽  
Amino Acid Variants

A highly conserved arginine residue is close to the catalytic center of PPM/PP2C-type protein phosphatases. Different crystal structures of PPM/PP2C homologues revealed that the guanidinium side chain of this arginine residue can adopt variable conformations and may bind ligands, suggesting an important role of this residue during catalysis. In this paper, we randomly mutated Arginine 13 of tPphA, a PPM/PP2C-type phosphatase from Thermosynechococcus elongatus, and obtained 18 different amino acid variants. The generated variants were tested towards p-nitrophenyl phosphate and various phosphopeptides. Towards p-nitrophenyl phosphate as substrate, twelve variants showed 3–7 times higher Km values than wild-type tPphA and four variants (R13D, R13F, R13L, and R13W) completely lost activity. Strikingly, these variants were still able to dephosphorylate phosphopeptides, although with strongly reduced activity. The specific inability of some Arg-13 variants to hydrolyze p-nitrophenyl phosphate highlights the importance of additional substrate interactions apart from the substrate phosphate for catalysis. The properties of the R13 variants indicate that this residue assists in substrate binding.

scholarly journals Daily oscillation of the excitation/inhibition ratio is disrupted in two mouse models of autism

2021 ◽  
Author(s):  
Michelle Bridi ◽  
Nancy Luo ◽  
Grace Kim ◽  
Caroline O'Ferrall ◽  
Ruchit Oatel ◽  
...  
Keyword(s):  
Mouse Models ◽  
Sensory Processing ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Behavioral State ◽  
Wild Type ◽  
Inhibitory Synaptic Transmission ◽  
Sleep Timing ◽  
Per Se ◽  
Daily Oscillation

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder involving sensory processing abnormalities. Alterations to the balance between excitation and inhibition (E/I ratio) are postulated to underlie behavioral phenotypes in ASD patients and mouse models. However, in primary visual cortex (V1) of wild type mice, the E/I ratio is not a fixed value, but rather oscillates across the 24h day. Therefore, we hypothesized that the E/I oscillation, rather than the overall E/I ratio, may be disrupted in ASD mouse models. To this end, we measured the E/I ratio in Fmr1 KO and BTBR mice, models of syndromic and idiopathic ASD, respectively. We found that the E/I ratio is dysregulated in both models, but in different ways: the oscillation is flattened in Fmr1 KO and phase-shifted in BTBR mice. These phenotypes cannot be explained by altered sleep timing, which was largely normal in both lines. Furthermore, we found that E/I dysregulation occurs due to alterations in both excitatory and inhibitory synaptic transmission in both models. These findings provide a crucial perspective on the E/I ratio in ASD, suggesting that ASD phenotypes may be produced by a mismatch of E/I to the appropriate behavioral state, rather than alterations to overall E/I levels per se.

scholarly journals Going beyond rote auditory learning: Neural patterns of generalized auditory learning

2021 ◽  
Author(s):  
Shannon L.M. Heald ◽  
Stephen C. Van Hedger ◽  
John Veillette ◽  
Katherine Reis ◽  
Joel S. Snyder ◽  
...  
Keyword(s):  
Speech Perception ◽  
Sensory Processing ◽  
Auditory Processing ◽  
Auditory Evoked Potentials ◽  
Brain Regions ◽  
Auditory Evoked Potential ◽  
Cortical Processing ◽  
Rote Learning ◽  
Neural Responses ◽  
Auditory Learning

AbstractThe ability to generalize rapidly across specific experiences is vital for robust recognition of new patterns, especially in speech perception considering acoustic-phonetic pattern variability. Behavioral research has demonstrated that listeners are rapidly able to generalize their experience with a talker’s speech and quickly improve understanding of a difficult-to-understand talker without prolonged practice, e.g., even after a single training session. Here, we examine the differences in neural responses to generalized versus rote learning in auditory cortical processing by training listeners to understand a novel synthetic talker using a Pretest-Posttest design with electroencephalography (EEG). Participants were trained using either (1) a large inventory of words where no words repeated across the experiment (generalized learning) or (2) a small inventory of words where words repeated (rote learning). Analysis of long-latency auditory evoked potentials at Pretest and Posttest revealed that while rote and generalized learning both produce rapid changes in auditory processing, the nature of these changes differed. In the context of adapting to a talker, generalized learning is marked by an amplitude reduction in the N1-P2 complex and by the presence of a late-negative (LN) wave in the auditory evoked potential following training. Rote learning, however, is marked only by temporally later source configuration changes. The early N1-P2 change, found only for generalized learning, suggests that generalized learning relies on the attentional system to reorganize the way acoustic features are selectively processed. This change in relatively early sensory processing (i.e. during the first 250ms) is consistent with an active processing account of speech perception, which proposes that the ability to rapidly adjust to the specific vocal characteristics of a new talker (for which rote learning is rare) relies on attentional mechanisms to adaptively tune early auditory processing sensitivity.Statement of SignificancePrevious research on perceptual learning has typically examined neural responses during rote learning: training and testing is carried out with the same stimuli. As a result, it is not clear that findings from these studies can explain learning that generalizes to novel patterns, which is critical in speech perception. Are neural responses to generalized learning in auditory processing different from neural responses to rote learning? Results indicate rote learning of a particular talker’s speech involves brain regions focused on the memory encoding and retrieving of specific learned patterns, whereas generalized learning involves brain regions involved in reorganizing attention during early sensory processing. In learning speech from a novel talker, only generalized learning is marked by changes in the N1-P2 complex (reflective of secondary auditory cortical processing). The results are consistent with the view that robust speech perception relies on the fast adjustment of attention mechanisms to adaptively tune auditory sensitivity to cope with acoustic variability.

scholarly journals Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control

2012 ◽  
Vol 92 (1) ◽  
pp. 193-235 ◽  
Author(s):  
Hanns Ulrich Zeilhofer ◽  
Hendrik Wildner ◽  
Gonzalo E. Yévenes
Keyword(s):  
Chronic Pain ◽  
Dorsal Horn ◽  
Sensory Processing ◽  
Temporal Discrimination ◽  
Sensory Nerve ◽  
Nerve Fibers ◽  
Sensory Stimuli ◽  
Inhibitory Neurotransmission ◽  
Pain Syndromes ◽  
Chronic Pain Syndromes

The two amino acids GABA and glycine mediate fast inhibitory neurotransmission in different CNS areas and serve pivotal roles in the spinal sensory processing. Under healthy conditions, they limit the excitability of spinal terminals of primary sensory nerve fibers and of intrinsic dorsal horn neurons through pre- and postsynaptic mechanisms, and thereby facilitate the spatial and temporal discrimination of sensory stimuli. Removal of fast inhibition not only reduces the fidelity of normal sensory processing but also provokes symptoms very much reminiscent of pathological and chronic pain syndromes. This review summarizes our knowledge of the molecular bases of spinal inhibitory neurotransmission and its organization in dorsal horn sensory circuits. Particular emphasis is placed on the role and mechanisms of spinal inhibitory malfunction in inflammatory and neuropathic chronic pain syndromes.

scholarly journals Acamprosate-responsive brain sites for suppression of ethanol intake and preference

2011 ◽  
Vol 301 (4) ◽  
pp. R1032-R1043 ◽  
Author(s):  
Allison Brager ◽  
Rebecca A. Prosser ◽  
J. David Glass
Keyword(s):  
Alcohol Intake ◽  
Free Choice ◽  
Clock Gene ◽  
Brain Regions ◽  
Ethanol Intake ◽  
Mutant Mice ◽  
Wild Type ◽  
Circadian Clock Gene ◽  
Recovering Alcoholics ◽  
Brain Reward

Acamprosate suppresses alcohol intake and craving in recovering alcoholics; however, the central sites of its action are unclear. To approach this question, brain regions responsive to acamprosate were mapped using acamprosate microimplants targeted to brain reward and circadian areas implicated in alcohol dependence. mPer2 mutant mice with nonfunctional mPer2, a circadian clock gene that gates endogenous timekeeping, were included, owing to their high levels of ethanol intake and preference. Male wild-type (WT) and mPer2 mutant mice received free-choice (15%) ethanol/water for 3 wk. The ethanol was withdrawn for 3 wk and then reintroduced to facilitate relapse. Four days before ethanol reintroduction, mice received bilateral blank or acamprosate-containing microimplants releasing ∼50 ng/day into reward [ventral tegmental (VTA), peduculopontine tegmentum (PPT), and nucleus accumbens (NA)] and circadian [intergeniculate leaflet (IGL) and suprachiasmatic nucleus (SCN)] areas. The hippocampus was also targeted. Circadian locomotor activity was measured throughout. Ethanol intake and preference were greater in mPer2 mutants than in wild-type (WT) mice (27 g·kg−1·day−1 vs. 13 g·kg−1·day−1 and 70% vs. 50%, respectively; both, P < 0.05). In WTs, acamprosate in all areas, except hippocampus, suppressed ethanol intake and preference (by 40–60%) during ethanol reintroduction. In mPer2 mutants, acamprosate in the VTA, PPT, and SCN suppressed ethanol intake and preference by 20–30%. These data are evidence that acamprosate's suppression of ethanol intake and preference are manifest through actions within major reward and circadian sites.

scholarly journals 4225 Evaluation of Neurotransmitters in Channelopathy-Related Epilepsy

2020 ◽  
Vol 4 (s1) ◽  
pp. 95-95
Author(s):  
Sunita N Misra ◽  
Theresa M. Czech ◽  
Jennifer A. Kearney
Keyword(s):  
Mouse Model ◽  
Chart Review ◽  
Retrospective Chart Review ◽  
Brain Regions ◽  
Autism Spectrum ◽  
Wild Type ◽  
Voltage Gated Sodium Channels ◽  
Study Population ◽  
Genotype A

OBJECTIVES/GOALS: Variants in voltage-gated sodium channels (VGSC) are a common cause of severe early onset epilepsy. Changes in CSF neurotransmitters (NT) were identified in 2 cases of VGSC-related epilepsy. Here we investigate NT changes in patients and a novel mouse model of VGSC-related epilepsy. METHODS/STUDY POPULATION: We conducted a single site IRB approved retrospective chart review of patients with VGSC-related epilepsy who underwent CSF NT testing for diagnostic purposes. In parallel, we examined NT levels from the brains of wild-type (WT) and a novel VGSC-related epilepsy mouse model after obtaining IACUC approval. We rapidly isolated forebrain, cortex, striatum, and brainstem from 5-6 animals per sex and genotype. A combination of HPLC with electrochemical detection and mass spectrometry were used to quantify NT levels from brain samples. RESULTS/ANTICIPATED RESULTS: We identified 10 patients with VGSC-related epilepsy who received CSF NT testing. Two of these patients had abnormal NT results including changes to dopamine (DA) or serotonin (5-HT) metabolites. We analyzed NT levels from four brain regions from male and female WT and VGSC-related epilepsy mice. We anticipate that most of the NT levels will be similar to WT, however subtle changes in the DA or 5-HT metabolites may be seen in VGSC-related epilepsy. DISCUSSION/SIGNIFICANCE OF IMPACT: Patients with VGSC-related epilepsy often have autism spectrum disorder, sleep, and movement disorders. Understanding the role of aberrant NT levels in VGSC-related epilepsy may provide additional therapeutic targets that address common neuropsychological comorbidities as well as seizures.

scholarly journals Neural Connectivity Subtypes Predict Discrete Attentional-Bias Profiles Among Heterogeneous Anxiety Patients

2020 ◽  
Vol 8 (3) ◽  
pp. 491-505 ◽  
Author(s):  
Rebecca B. Price ◽  
Adriene M. Beltz ◽  
Mary L. Woody ◽  
Logan Cummings ◽  
Danielle Gilchrist ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Selective Attention ◽  
Attentional Bias ◽  
Sensory Processing ◽  
Brain Regions ◽  
Data Driven ◽  
Neural Connectivity ◽  
Group Level ◽  
Behavioral Measures ◽  
Substantial Heterogeneity

On average, anxious patients show altered attention to threat—including early vigilance toward threat and later avoidance of threat—accompanied by altered functional connectivity across brain regions. However, substantial heterogeneity within clinical, neural, and attentional features of anxiety is overlooked in typical group-level comparisons. We used a well-validated method for data-driven parsing of neural connectivity to reveal connectivity-based subgroups among 60 adults with transdiagnostic anxiety. Subgroups were externally compared on attentional patterns derived from independent behavioral measures. Two subgroups emerged. Subgroup A (68% of patients) showed stronger executive network influences on sensory processing regions and a paradigmatic “vigilance–avoidance” pattern on external behavioral measures. Subgroup B was defined by a larger number of limbic influences on sensory regions and exhibited a more atypical and inconsistent attentional profile. Neural connectivity-based categorization revealed an atypical, limbic-driven pattern of connectivity in a subset of anxious patients that generalized to atypical patterns of selective attention.

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