Female-specific dysfunction of sensory neocortical circuits in a mouse model of autism mediated by mGluR5 and estrogen receptor α

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 114056 - 114056

Published: April 1, 2024

Little is known of the brain mechanisms that mediate sex-specific autism symptoms. Here, we demonstrate deletion spectrum disorder (ASD)-risk gene, Pten, in neocortical pyramidal neurons (

Language: Английский

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Neural Adaptation at Stimulus Onset and Speed of Neural Processing as Critical Contributors to Speech Comprehension Independent of Hearing Threshold or Age

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(9), P. 2725 - 2725

Published: May 6, 2024

Background: It is assumed that speech comprehension deficits in background noise are caused by age-related or acquired hearing loss. Methods: We examined young, middle-aged, and older individuals with without threshold loss using pure-tone (PT) audiometry, short-pulsed distortion-product otoacoustic emissions (pDPOAEs), auditory brainstem responses (ABRs), steady-state (ASSRs), (OLSA), syllable discrimination quiet noise. Results: A noticeable decline of sensitivity extended high-frequency regions its influence on low-frequency-induced ABRs was striking. When testing for differences OLSA thresholds normalized PT (PTTs), marked ability exist not only noise, but also quiet, they throughout the whole age range investigated. Listeners poor exhibited a relatively lower pDPOAE and, thus, cochlear amplifier performance independent PTT, smaller delayed ABRs, vowel-phoneme below phase-locking limits (/o/-/u/). tested listeners PTT had larger pDPOAEs performance, ASSR amplitudes, higher uncomfortable loudness levels, all linked above limit (/i/-/y/). Conslusions: This study indicates listening humans has sizable disadvantage envelope coding when basilar-membrane compression compromised. Clearly, contrast to previous assumptions, both good can independently PTTs age, phenomenon urgently requires improved techniques diagnose sound processing at stimulus onset clinical routine.

Language: Английский

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Developmental delays in cortical auditory temporal processing in a mouse model of Fragile X syndrome

Journal of Neurodevelopmental Disorders, Journal Year: 2023, Volume and Issue: 15(1)

Published: July 29, 2023

Abstract Background Autism spectrum disorders (ASD) encompass a wide array of debilitating symptoms, including sensory dysfunction and delayed language development. Auditory temporal processing is crucial for speech perception Abnormal development may account the impairments associated with ASD. Very little known about in any animal model Methods In current study, we quantify auditory throughout Fmr1 knock-out (KO) mouse Fragile X Syndrome (FXS), leading genetic cause intellectual disability ASD-associated behaviors. Using epidural electrodes awake freely moving wildtype (WT) KO mice, recorded event related potentials (ERP) gap-in-noise steady state response (gap-ASSR) paradigm. Mice were at three different ages cross sectional design: postnatal (p)21, p30 p60. Recordings obtained from both frontal cortices. The gap-ASSR requires underlying neural generators to synchronize responses gaps widths embedded noise, providing an objective measure across genotypes age groups. Results We present evidence that frontal, but not auditory, cortex shows significant deficits p21 p30, poor ability phase lock rapid noise. Temporal was similar adult mice. ERP amplitudes larger mice cortex, consistent data humans FXS. Conclusions These indicate cortical region-specific delays Developmental follow changes sounds shape FXS, more broadly

Language: Английский

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Acute administration of NLX-101, a Serotonin 1A receptor agonist, improves auditory temporal processing during development in a mouse model of Fragile X Syndrome

Journal of Neurodevelopmental Disorders, Journal Year: 2025, Volume and Issue: 17(1)

Published: Jan. 3, 2025

Abstract Background Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent debilitating phenotype FXS auditory hypersensitivity that may lead to delayed language high anxiety. Consistent with findings in human studies, the mouse model FXS, Fmr1 knock out (KO) mouse, shows temporal processing deficits. In electroencephalograph (EEG) recordings from humans mice, these deficits manifest as increased N1 amplitudes event-related potentials (ERP), gamma band single trial power (STP) reduced phase locking rapid modulations sound. our previous study, we found administration selective serotonin-1 (5-HT 1A )receptor biased agonist, NLX-101, protected KO mice hypersensitivity-associated seizures. Here tested hypothesis NLX-101 will normalize EEG phenotypes developing mice. Methods To test this hypothesis, examined effect on male female wildtype (WT) Using epidural electrodes, recorded event related (ERP) gap-in-noise steady state response (ASSR) paradigm at two ages, postnatal (P) 21 30 days, both frontal cortices awake, freely moving following (at 1.8 mg/kg i.p.) or saline administration. Results Saline-injected showed amplitudes, STP stimuli versus wild-type reproducing previously published phenotypes. An acute injection did not alter ERP either P21 P30, but significantly reduces P30. Inter-trial clustering was age groups indicating improved processing. The differential effects serotonin modulation ERP, background suggest different developmental mechanisms Conclusions These results could constitute promising treatment option for targeting post-synaptic 5-HT receptors improve processing, which turn speech function FXS.

Language: Английский

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Auditory evoked-potential abnormalities in a mouse model of 22q11.2 Deletion Syndrome and their interactions with hearing impairment

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 8, 2025

Abstract The 22q11.2 deletion is a risk factor for multiple psychiatric disorders including schizophrenia and also increases vulnerability to middle-ear problems that can cause hearing impairment. Up 60% of carriers experience impairment ~30% develop in adulthood. It not known if these risks interact. Here we used the Df1/+ mouse model investigate how might interact with increased genetic disease affect brain function. We measured function using cortical auditory evoked potentials (AEPs), which are commonly non-invasively humans. After identifying one simplest best-validated methods AEP measurement mice from diversity previous approaches, peripheral sensitivity AEPs their WT littermates. exploited large inter-individual variation ability among distinguish effects background Central gain adaptation were quantified by comparing brainstem activity analyzing growth increasing sound level or inter-tone interval duration. found level-dependent was abnormally regardless impairment, but other measures central depended on both genotype phenotype. Our results demonstrate relevance comorbid loss dysfunction 22q11.2DS identify potential biomarkers robust

Language: Английский

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Perineuronal net degradation causes a delayed change in resting and sound evoked responses in the mouse auditory cortex

Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

Language: Английский

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Cortical layer-specific abnormalities in auditory responses in a mouse model of Fragile X Syndrome

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106963 - 106963

Published: May 1, 2025

Fragile X Syndrome (FXS) is a leading genetic cause of autism spectrum disorders (ASD)- associated behaviors, including sensory processing deficits. Sensory sensitivity and temporal deficits in the auditory domain will affect development language cognitive functions. The mouse model for FXS, Fmr1 KO, has shown remarkably similar phenotypes to patients with FXS. In vitro cortical slice recordings show layer-specific differences KO local circuits, but it unclear how these translate changes processing. this study, we used depth multielectrode record vivo spikes field potentials across layers cortex wildtype mice (WT), converting latter current source density (CSD) profiles improved spatial resolution analysis. We observe reduced CSD sink amplitudes inter-trial phase coherence, an increase trial-to-trial variability temporally modulated stimuli mice. Results indicate differential layer pattern activity mice, higher baseline gamma power superficial deep resting delta theta granular layers. Significantly elevated was observed Auditory steady state responses clicks or gaps at 40 Hz showed considerable manner Neural generators failed detect short noise, indicating severe Altogether, study indicates mechanisms hypersensitivity

Language: Английский

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Sex differences during development in cortical temporal processing and event related potentials in wild-type and fragile X syndrome model mice

Journal of Neurodevelopmental Disorders, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 8, 2024

Abstract Background Autism spectrum disorder (ASD) is currently diagnosed in approximately 1 44 children the United States, based on a wide array of symptoms, including sensory dysfunction and abnormal language development. Boys are ~ 3.8 times more frequently than girls. Auditory temporal processing crucial for speech recognition Abnormal development may account ASD impairments. Sex differences underlie outcomes male female with ASD. To understand mechanisms potential sex requires preclinical model. However, there no studies that have addressed across any animal model Methods fill this major gap, we compared auditory wildtype (WT) Fmr1 knock-out (KO) mice, Fragile X Syndrome (FXS), leading genetic cause ASD-associated behaviors. Using epidural screw electrodes, recorded event related potentials (ERP) gap-in-noise steady state response (ASSR) paradigm at young (postnatal (p)21 p30) adult (p60) ages from both frontal cortices awake, freely moving mice. Results The results show ERP amplitudes were enhanced sexes KO mice to WT counterparts, greater enhancement Gap-ASSR deficits seen frontal, but not auditory, cortex early (p21) Unlike WT-like p30. There sexes. Conclusions These difference developmental trajectories hypersensitive responses Male slower maturation females. Female stronger males later rates during various critical periods lead function, arousal anxiety FXS.

Language: Английский

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Developmental trajectory and sex differences in auditory processing in a PTEN-deletion model of autism spectrum disorders

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 200, P. 106628 - 106628

Published: Aug. 5, 2024

Autism Spectrum Disorders (ASD) encompass a wide array of debilitating symptoms, including severe sensory deficits and abnormal language development. Sensory early in development may lead to broader symptomatology adolescents adults. The mechanistic links between ASD risk genes, processing impairment are unclear. There is also sex bias diagnosis symptomatology. current study aims identify the developmental trajectory genotype- sex-dependent differences auditory sensitivity temporal Pten-deletion (phosphatase tensin homolog missing on chromosome 10) mouse model ASD. Auditory crucial for speech recognition will cause impairments. However, very little known about animal models, if there differences. To address this major gap, we recorded epidural electroencephalography (EEG) signals from frontal (FC) (AC) cortex developing adult Nse-cre PTEN mice, which Pten deleted specific cortical layers (layers III-V) (PTEN conditional knock-out (cKO). We quantified resting EEG spectral power distribution, event related potentials (ERP) awake freely moving male female mice. Temporal measured using gap-in-noise-ASSR (auditory steady state response) stimulus paradigm. experimental manipulation gap duration modulation depth allows us measure entrainment rapid gaps sounds. was inter-trial phase clustering (ITPC) values that account consistency across trials. results show genotype distribution cKO mice throughout Male have significantly increased beta but decreased high frequency oscillations AC FC. Both diminished ITPC their gap-ASSR responses FC compared control Overall, become more prominent (p60) with having sound evoked controls. While both demonstrated development, showed hypersensitivity males, reflected as N1 P2 amplitudes. These data number novel PTEN-ASD present an age. Abnormal hypersensitive contribute function

Language: Английский

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Cortical region-specific recovery of auditory temporal processing following noise-induced hearing loss

Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Language: Английский

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