scholarly journals Altered brain-wide auditory networks in fmr1-mutant larval zebrafish

2019 ◽  
Author(s):  
Lena Constantin ◽  
Rebecca E. Poulsen ◽  
Itia A. Favre-Bulle ◽  
Michael A. Taylor ◽  
Biao Sun ◽  
...  
Keyword(s):  
Graph Theory ◽  
Sensory Processing ◽  
Calcium Imaging ◽  
Fragile X ◽  
Auditory Information ◽  
Wild Type ◽  
Larval Zebrafish ◽  
Cellular Resolution ◽  
Psychiatric Conditions ◽  
Functional Analyses

Altered sensory processing is characteristic of several psychiatric conditions, including autism and fragile X syndrome (FXS). Here, we use whole-brain calcium imaging at cellular resolution to map sensory processing in wild type larval zebrafish and mutants for fmr1, which causes FXS in humans. Using functional analyses and graph theory, we describe increased transmission and reduced filtering of auditory information, resulting in network-wide hypersensitivity analogous to the auditory phenotypes seen in FXS.

scholarly journals Brain-wide visual habituation networks in wild type and fmr1 zebrafish

2019 ◽  
Author(s):  
Emmanuel Marquez-Legorreta ◽  
Lena Constantin ◽  
Marielle Piber ◽  
Itia A. Favre-Bulle ◽  
Michael A. Taylor ◽  
...  
Keyword(s):  
Fragile X ◽  
Brain Activity ◽  
Visual Learning ◽  
Behavioral Habituation ◽  
Cellular Resolution ◽  
Stimulus Saliency ◽  
Systematic Shift ◽  
Psychiatric Conditions ◽  
Visual Habituation ◽  
The Brain

AbstractHabituation is a form of learning during which animals stop responding to repetitive stimuli, and deficits in habituation are characteristics of several psychiatric disorders. Due to the technical challenges of measuring brain activity comprehensively and at cellular resolution, the brain-wide networks mediating habituation are poorly understood. Here we report brain-wide calcium imaging during visual learning in larval zebrafish as they habituate to repeated threatening loom stimuli. We show that different functional categories of loom-sensitive neurons are located in characteristic locations throughout the brain, and that both the functional properties of their networks and the resulting behavior can be modulated by stimulus saliency and timing. Using graph theory, we identify a principally visual circuit that habituates minimally, a moderately habituating midbrain population proposed to mediate the sensorimotor transformation, and downstream circuit elements responsible for higher order representations and the delivery of behavior. Zebrafish larvae carrying a mutation in the fmr1 gene have a systematic shift towards sustained premotor activity in this network, and show slower behavioral habituation. This represents the first description of a visual learning network across the brain at cellular resolution, and provides insights into the circuit-level changes that may occur in people with Fragile X syndrome and related psychiatric conditions.

scholarly journals Altered brain-wide auditory networks in a zebrafish model of fragile X syndrome

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lena Constantin ◽  
Rebecca E. Poulsen ◽  
Leandro A. Scholz ◽  
Itia A. Favre-Bulle ◽  
Michael A. Taylor ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Visual Motion ◽  
Fragile X ◽  
Auditory Pathway ◽  
Brain Regions ◽  
Torus Semicircularis ◽  
Auditory Stimuli ◽  
Auditory Information ◽  
Zebrafish Model ◽  
Cellular Resolution

Abstract Background Loss or disrupted expression of the FMR1 gene causes fragile X syndrome (FXS), the most common monogenetic form of autism in humans. Although disruptions in sensory processing are core traits of FXS and autism, the neural underpinnings of these phenotypes are poorly understood. Using calcium imaging to record from the entire brain at cellular resolution, we investigated neuronal responses to visual and auditory stimuli in larval zebrafish, using fmr1 mutants to model FXS. The purpose of this study was to model the alterations of sensory networks, brain-wide and at cellular resolution, that underlie the sensory aspects of FXS and autism. Results Combining functional analyses with the neurons’ anatomical positions, we found that fmr1−/− animals have normal responses to visual motion. However, there were several alterations in the auditory processing of fmr1−/− animals. Auditory responses were more plentiful in hindbrain structures and in the thalamus. The thalamus, torus semicircularis, and tegmentum had clusters of neurons that responded more strongly to auditory stimuli in fmr1−/− animals. Functional connectivity networks showed more inter-regional connectivity at lower sound intensities (a − 3 to − 6 dB shift) in fmr1−/− larvae compared to wild type. Finally, the decoding capacities of specific components of the ascending auditory pathway were altered: the octavolateralis nucleus within the hindbrain had significantly stronger decoding of auditory amplitude while the telencephalon had weaker decoding in fmr1−/− mutants. Conclusions We demonstrated that fmr1−/− larvae are hypersensitive to sound, with a 3–6 dB shift in sensitivity, and identified four sub-cortical brain regions with more plentiful responses and/or greater response strengths to auditory stimuli. We also constructed an experimentally supported model of how auditory information may be processed brain-wide in fmr1−/− larvae. Our model suggests that the early ascending auditory pathway transmits more auditory information, with less filtering and modulation, in this model of FXS.

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 Single-molecule imaging of translational output from individual RNA granules in neurons

2012 ◽  
Vol 23 (5) ◽  
pp. 918-929 ◽  
Author(s):  
Vedakumar Tatavarty ◽  
Marius F. Ifrim ◽  
Mikhail Levin ◽  
George Korza ◽  
Elisa Barbarese ◽  
...  
Keyword(s):  
Single Molecule ◽  
Fluorescent Protein ◽  
Fragile X ◽  
Single Molecule Imaging ◽  
Wild Type ◽  
Rna Molecules ◽  
Temporal Regulation ◽  
Rna Granules ◽  
Mental Retardation Protein ◽  
Insight Into

Dendritic RNAs are localized and translated in RNA granules. Here we use single-molecule imaging to count the number of RNA molecules in each granule and to record translation output from each granule using Venus fluorescent protein as a reporter. For RNAs encoding activity-regulated cytoskeletal-associated protein (ARC) or fragile X mental retardation protein (FMRP), translation events are spatially clustered near individual granules, and translational output from individual granules is either sporadic or bursty. The probability of bursty translation is greater for Venus-FMRP RNA than for Venus-ARC RNA and is increased in Fmr1-knockout neurons compared to wild-type neurons. Dihydroxyphenylglycine (DHPG) increases the rate of sporadic translation and decreases bursty translation for Venus-FMRP and Venus-ARC RNAs. Single-molecule imaging of translation in individual granules provides new insight into molecular, spatial, and temporal regulation of translation in granules.

scholarly journals Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 13 ◽  
Author(s):  
Chloé Felgerolle ◽  
Betty Hébert ◽  
Maryvonne Ardourel ◽  
Géraldine Meyer-Dilhet ◽  
Arnaud Menuet ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Visual Behavior

scholarly journals GABA Measurement in a Neonatal Fragile X Syndrome Mouse Model Using 1H-Magnetic Resonance Spectroscopy and Mass Spectrometry

2020 ◽  
Vol 13 ◽  
Author(s):  
Samantha T. Reyes ◽  
Sanaz Mohajeri ◽  
Karolina Krasinska ◽  
Scarlett G. Guo ◽  
Meng Gu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Magnetic Resonance ◽  
Frontal Cortex ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Gabaergic System ◽  
Wild Type ◽  
Gaba Concentration ◽  
Non Invasive

Fragile X syndrome (FXS) is the leading monogenetic cause of autism spectrum disorder and inherited cause of intellectual disability that affects approximately one in 7,000 males and one in 11,000 females. In FXS, the Fmr1 gene is silenced and prevents the expression of the fragile X mental retardation protein (FMRP) that directly targets mRNA transcripts of multiple GABAA subunits. Therefore, FMRP loss adversely impacts the neuronal firing of the GABAergic system which creates an imbalance in the excitatory/inhibitory ratio within the brain. Current FXS treatment strategies focus on curing symptoms, such as anxiety or decreased social function. While treating symptoms can be helpful, incorporating non-invasive imaging to evaluate how treatments change the brain’s biology may explain what molecular aberrations are associated with disease pathology. Thus, the GABAergic system is suitable to explore developing novel therapeutic strategies for FXS. To understand how the GABAergic system may be affected by this loss-of-function mutation, GABA concentrations were examined within the frontal cortex and thalamus of 5-day-old wild type and Fmr1 knockout mice using both 1H magnetic resonance imaging (1H-MRS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our objective was to develop a reliable scanning method for neonatal mice in vivo and evaluate whether 1H-MRS is suitable to capture regional GABA concentration differences at the front end of the critical cortical period where abnormal neurodevelopment occurs due to FMRP loss is first detected. 1H-MRS quantified GABA concentrations in both frontal cortex and thalamus of wild type and Fmr1 knockout mice. To substantiate the results of our 1H-MRS studies, in vitro LC-MS/MS was also performed on brain homogenates from age-matched mice. We found significant changes in GABA concentration between the frontal cortex and thalamus within each mouse from both wild type and Fmr1 knockout mice using 1H-MRS and LC-MS/MS. Significant GABA levels were also detected in these same regions between wild type and Fmr1 knockout mice by LC-MS/MS, validating that FMRP loss directly affects the GABAergic system. Thus, these new findings support the need to develop an effective non-invasive imaging method to monitor novel GABAergic strategies aimed at treating patients with FXS.

scholarly journals Stability of the Human Fragile X (CGG)n Triplet Repeat Array inSaccharomyces cerevisiae Deficient in Aspects of DNA Metabolism

1999 ◽  
Vol 19 (8) ◽  
pp. 5675-5684 ◽  
Author(s):  
Peter J. White ◽  
Rhona H. Borts ◽  
Mark C. Hirst
Keyword(s):  
Germ Line ◽  
Fragile X ◽  
Low Frequency ◽  
Triplet Repeat ◽  
Dependent Manner ◽  
Wild Type ◽  
Specific Expression ◽  
Repeat Array ◽  
Cellular Environment ◽  
Length Changes

ABSTRACT Expanded trinucleotide repeats underlie a growing number of human diseases. The human FMR1 (CGG) n array can exhibit genetic instability characterized by progressive expansion over several generations leading to gene silencing and the development of the fragile X syndrome. While expansion is dependent upon the length of uninterrupted (CGG) n , instability occurs in a limited germ line and early developmental window, suggesting that lineage-specific expression of other factors determines the cellular environment permissive for expansion. To identify these factors, we have established normal- and premutation-length human FMR1 (CGG) n arrays in the yeast Saccharomyces cerevisiae and assessed the frequency of length changes greater than 5 triplets in cells deficient in various DNA repair and replication functions. In contrast to previous studies withEscherichia coli, we observed a low frequency of orientation-dependent large expansions in arrays carrying long uninterrupted (CGG) n arrays in a wild-type background. This frequency was unaffected by deletion of several DNA mismatch repair genes or deletion of the EXO1 andDIN7 genes and was not enhanced through meiosis in a wild-type background. Array contraction occurred in an orientation-dependent manner in most mutant backgrounds, but loss of the Sgs1p resulted in a generalized increase in array stability in both orientations. In contrast, FMR1 arrays had a 10-fold-elevated frequency of expansion in a rad27 background, providing evidence for a role in lagging-strand Okazaki fragment processing in (CGG) n triplet repeat expansion.

scholarly journals Detection of long repeat expansions from PCR-free whole-genome sequence data

2016 ◽  
Author(s):  
Egor Dolzhenko ◽  
Joke J.F.A. van Vugt ◽  
Richard J. Shaw ◽  
Mitchell A. Bekritsky ◽  
Marka van Blitterswijk ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Sequence Data ◽  
Fragile X ◽  
Software Tool ◽  
Whole Genome Sequence ◽  
Read Length ◽  
Whole Genome ◽  
Wild Type ◽  
Short Read ◽  
Repeat Expansions

AbstractIdentifying large repeat expansions such as those that cause amyotrophic lateral sclerosis (ALS) and Fragile X syndrome is challenging for short-read (100-150 bp) whole genome sequencing (WGS) data. A solution to this problem is an important step towards integrating WGS into precision medicine. We have developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3,001 ALS patients who have been tested for the presence of the C9orf72 repeat expansion with repeat-primed PCR (RP-PCR). Taking the RP-PCR calls as the ground truth, our WGS-based method identified pathogenic repeat expansions with 98.1% sensitivity and 99.7% specificity. Further inspection identified that all 11 conflicts were resolved as errors in the original RP-PCR results. Compared against this updated result, ExpansionHunter correctly classified all (212/212) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2,786/2,789) of the wild type samples were correctly classified as wild type by this method with the remaining two identified as possible expansions. We further applied our algorithm to a set of 144 samples where every sample had one of eight different pathogenic repeat expansions including examples associated with fragile X syndrome, Friedreich’s ataxia and Huntington’s disease and correctly flagged all of the known repeat expansions. Finally, we tested the accuracy of our method for short repeats by comparing our genotypes with results from 860 samples sized using fragment length analysis and determined that our calls were >95% accurate. ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.

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