scholarly journals Auditory Hypersensitivity and Processing Deficits in a Rat Model of Fragile X Syndrome

2021 ◽  
Author(s):  
Benjamin D Auerbach ◽  
Senthilvelan Manohar ◽  
Kelly Radziwon ◽  
Richard Salvi
Keyword(s):  
Auditory System ◽  
Rat Model ◽  
Auditory Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sound Perception ◽  
Sensory Hypersensitivity ◽  
Spectral Integration ◽  
Processing Deficits ◽  
Loudness Growth

Fragile X (FX) syndrome is one of the leading inherited causes of autism spectrum disorder (ASD). A majority of FX and ASD patients exhibit sensory hypersensitivity, including auditory hypersensitivity or hyperacusis, a condition in which everyday sounds are perceived as much louder than normal. Auditory processing deficits in FX and ASD also afford the opportunity to develop objective and quantifiable outcome measures that are likely to translate between humans and animal models due to the well-conserved nature of the auditory system and well-developed behavioral read-outs of sound perception. Therefore, in this study we characterized auditory hypersensitivity in a Fmr1 knockout (KO) transgenic rat model of FX using an operant conditioning task to assess sound detection thresholds and suprathreshold auditory reaction time-intensity (RT-I) functions, a reliable psychoacoustic measure of loudness growth, at a variety of stimulus frequencies, bandwidths and durations. Male Fmr1 KO and littermate WT rats both learned the task at the same rate and exhibited normal hearing thresholds. However, Fmr1 KO rats had faster auditory RTs over a broad range of intensities and steeper RT-I slopes than WT controls, perceptual evidence of excessive loudness growth in Fmr1 KO rats. Furthermore, we found that Fmr1 KO animals exhibited abnormal perceptual integration of sound duration and bandwidth, with diminished temporal but enhanced spectral integration of sound intensity. Because temporal and spectral integration of sound stimuli were altered in opposite directions in Fmr1 KO rats, this suggests that abnormal RTs in these animals are evidence of aberrant auditory processing rather than generalized hyperactivity or altered motor responses. Together, these results are indicative of fundamental changes to low-level auditory processing in Fmr1 KO animals. Finally, we demonstrated that antagonism of metabotropic glutamate receptor 5 (mGlu5) selectively and dose-dependently restored normal loudness growth in Fmr1 KO rats, suggesting a pharmacologic approach for alleviating sensory hypersensitivity associated with FX. This study leverages the tractable nature of the auditory system and the unique behavioral advantages of rats to provide important insights into the nature of a centrally important yet understudied aspect of FX and ASD.

scholarly journals Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

2021 ◽  
Author(s):  
Chaojuan Yang ◽  
Yonglu Tian ◽  
Feng Su ◽  
Yangzhen Wang ◽  
Mengna Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Visual Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Local Network ◽  
V1 Neurons ◽  
Processing Deficits

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

scholarly journals Auditory hypersensitivity and processing deficits in a rat model of fragile X syndrome

2021 ◽  
pp. 105541
Author(s):  
BenjaminD. Auerbach ◽  
Senthilvelan Manohar ◽  
Kelly Radziwon ◽  
Richard Salvi
Keyword(s):  
Fragile X Syndrome ◽  
Rat Model ◽  
Fragile X ◽  
Processing Deficits

scholarly journals Mechanisms underlying auditory processing deficits in Fragile X syndrome

2020 ◽  
Vol 34 (3) ◽  
pp. 3501-3518 ◽  
Author(s):  
Elizabeth A. McCullagh ◽  
Sarah E. Rotschafer ◽  
Benjamin D. Auerbach ◽  
Achim Klug ◽  
Leonard K. Kaczmarek ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Auditory Processing ◽  
Fragile X ◽  
Processing Deficits

scholarly journals Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

2021 ◽  
Author(s):  
Antonis Asiminas ◽  
Sam A Booker ◽  
Owen R Dando ◽  
Zrinko Kozic ◽  
Daisy Arkell ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Rat Model ◽  
Pyramidal Neurons ◽  
Fragile X ◽  
Autism Spectrum ◽  
Oscillatory Activity ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Spatial Tuning ◽  
Cognitive Inflexibility

Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and Autism Spectrum Disorder. Cognitive inflexibility is one of the hallmarks of FXS, with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1 KO), and recorded from the CA1 region of the hippocampus while animals habituated in a novel environment for two consecutive days. On the first day of exploration, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1 KO rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1 KO rats. These findings were consistent with increased excitability of Fmr1 KO CA1 neurons in ex-vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were discoordinated with respect to hippocampal oscillatory activity in Fmr1 KO rats. These findings suggest a network-level origin of cognitive deficits in FXS.

scholarly journals Deletion of Fmr1 from Forebrain Excitatory Neurons Triggers Abnormal Cellular, EEG, and Behavioral Phenotypes in the Auditory Cortex of a Mouse Model of Fragile X Syndrome

2019 ◽  
Vol 30 (3) ◽  
pp. 969-988 ◽  
Author(s):  
Jonathan W Lovelace ◽  
Maham Rais ◽  
Arnold R Palacios ◽  
Xinghao S Shuai ◽  
Steven Bishay ◽  
...  
Keyword(s):  
Mouse Model ◽  
Auditory Cortex ◽  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Behavioral Phenotypes ◽  
Excitatory Neurons ◽  
Gamma Power ◽  
Processing Deficits

Abstract Fragile X syndrome (FXS) is a leading genetic cause of autism with symptoms that include sensory processing deficits. In both humans with FXS and a mouse model [Fmr1 knockout (KO) mouse], electroencephalographic (EEG) recordings show enhanced resting state gamma power and reduced sound-evoked gamma synchrony. We previously showed that elevated levels of matrix metalloproteinase-9 (MMP-9) may contribute to these phenotypes by affecting perineuronal nets (PNNs) around parvalbumin (PV) interneurons in the auditory cortex of Fmr1 KO mice. However, how different cell types within local cortical circuits contribute to these deficits is not known. Here, we examined whether Fmr1 deletion in forebrain excitatory neurons affects neural oscillations, MMP-9 activity, and PV/PNN expression in the auditory cortex. We found that cortical MMP-9 gelatinase activity, mTOR/Akt phosphorylation, and resting EEG gamma power were enhanced in CreNex1/Fmr1Flox/y conditional KO (cKO) mice, whereas the density of PV/PNN cells was reduced. The CreNex1/Fmr1Flox/y cKO mice also show increased locomotor activity, but not the anxiety-like behaviors. These results indicate that fragile X mental retardation protein changes in excitatory neurons in the cortex are sufficient to elicit cellular, electrophysiological, and behavioral phenotypes in Fmr1 KO mice. More broadly, these results indicate that local cortical circuit abnormalities contribute to sensory processing deficits in autism spectrum disorders.

Patterns of Auditory Processing and Articulation Deficits in Academically Deficient Juvenile Delinquents

1983 ◽  
Vol 48 (1) ◽  
pp. 36-40 ◽  
Author(s):  
Peter W. Zinkus ◽  
Marvin I. Gottlieb
Keyword(s):  
Auditory Processing ◽  
Juvenile Delinquents ◽  
Language Disorders ◽  
Treatment Programs ◽  
Early School ◽  
Articulation Disorders ◽  
Processing Deficits ◽  
Academically Deficient ◽  
School Period ◽  
Speech And Language Disorders

Auditory processing deficits and articulation disorders were studied in a group of male juvenile delinquents. Significant auditory processing deficits were frequently observed and were significantly related to underachievement in reading, spelling, and arithmetic. In addition, articulation disorders were present in over 60% of the delinquent subjects. The results are interpreted to indicate that the evaluation of speech capabilities and auditory processing skills should be an integral part of treatment programs for delinquent populations. The importance of early intervention through identification and treatment of speech and language disorders in the early school period is supported.

Neuromodulatory Feedback to the Inferior Colliculus

2018 ◽  
pp. 576-610 ◽  
Author(s):  
Laura Hurley
Keyword(s):  
Inferior Colliculus ◽  
Auditory System ◽  
Auditory Processing ◽  
Internal State ◽  
Brain Regions ◽  
Auditory Information ◽  
Situational Variables ◽  
Acoustic Stimuli ◽  
Functionally Diverse ◽  
Behavioral Information

The inferior colliculus (IC) receives prominent projections from centralized neuromodulatory systems. These systems include extra-auditory clusters of cholinergic, dopaminergic, noradrenergic, and serotonergic neurons. Although these modulatory sites are not explicitly part of the auditory system, they receive projections from primary auditory regions and are responsive to acoustic stimuli. This bidirectional influence suggests the existence of auditory-modulatory feedback loops. A characteristic of neuromodulatory centers is that they integrate inputs from anatomically widespread and functionally diverse sets of brain regions. This connectivity gives neuromodulatory systems the potential to import information into the auditory system on situational variables that accompany acoustic stimuli, such as context, internal state, or experience. Once released, neuromodulators functionally reconfigure auditory circuitry through a variety of receptors expressed by auditory neurons. In addition to shaping ascending auditory information, neuromodulation within the IC influences behaviors that arise subcortically, such as prepulse inhibition of the startle response. Neuromodulatory systems therefore provide a route for integrative behavioral information to access auditory processing from its earliest levels.

scholarly journals Early differences in auditory processing relate to Autism Spectrum Disorder traits in infants with Neurofibromatosis Type I

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jannath Begum-Ali ◽  
◽  
Anna Kolesnik-Taylor ◽  
Isabel Quiroz ◽  
Luke Mason ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Auditory Processing ◽  
Neurofibromatosis Type ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Type I ◽  
Sensory Reactivity ◽  
Auditory Responses ◽  
Repetition Suppression ◽  
Age Related

Abstract Background Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies. Methods In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD. Results In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits. Conclusions These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.

scholarly journals Local Protein Translation and RNA Processing of Synaptic Proteins in Autism Spectrum Disorder

2021 ◽  
Vol 22 (6) ◽  
pp. 2811
Author(s):  
Yuyoung Joo ◽  
David R. Benavides
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Protein Translation ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Synaptic Proteins ◽  
Local Translation ◽  
Translation Control

Autism spectrum disorder (ASD) is a heritable neurodevelopmental condition associated with impairments in social interaction, communication and repetitive behaviors. While the underlying disease mechanisms remain to be fully elucidated, dysfunction of neuronal plasticity and local translation control have emerged as key points of interest. Translation of mRNAs for critical synaptic proteins are negatively regulated by Fragile X mental retardation protein (FMRP), which is lost in the most common single-gene disorder associated with ASD. Numerous studies have shown that mRNA transport, RNA metabolism, and translation of synaptic proteins are important for neuronal health, synaptic plasticity, and learning and memory. Accordingly, dysfunction of these mechanisms may contribute to the abnormal brain function observed in individuals with autism spectrum disorder (ASD). In this review, we summarize recent studies about local translation and mRNA processing of synaptic proteins and discuss how perturbations of these processes may be related to the pathophysiology of ASD.

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