Cochlear Synaptopathy Following Noise Exposure in Guinea Pigs: Its Electrophysiological and Histological Assessments

Exposure to high level of noise,may cause the permanent cochlear synaptic degeneration.In present study,a model of noise induced cochlear synaptopathy was established and the electrophysiological and histological metrics for its assessment was designed.6 guinea pigs were subjected to a synaptopathic noise(octave band of 4 kHz at 104 dB SPL,for 2-h).The amplitude growth curve of Auditory Brainstem Response(ABR)wave-I and wave-III latency shift in presence of noise were calculated.These indexes were considered in pre-exposure,1 day post exposure(1DPE),1 week post exposure(1WPE)and 1 month post exposure(1MPE)to noise.Finally,the samples were histologically analyzed.ABR wave-I amplitude was different between pre and 1DPE(p-value≤0.05).However,at 1WPE,it was recovered at low intensities but at 70 dB SPL and above,the differences persisted even till 1MPE.In masked ABR,the latency shift of wave-III was different between pre and 3 post exposure assessments(p-value≤0.05).Electro-microscopic analysis confirmed the synaptic degeneration,as the ribbons were larger than normal,hollow inside,and spherical and irregular in shape,also,the post synaptic density was abnormally thick and missed its flat orientation.These data revealed that noise at level below that can produce permanent hearing loss,can incur synaptic injury.So,noise is considered to be more damaging than previously thought.Accordingly,designing tools for clinical assessment of synaptopathy is beneficial in comprehensive auditory evaluation of those with history of noise exposure and also in hearing protection planning.

Physical exercise and synaptic protection in human and pre-clinical models of multiple sclerosis

In multiple sclerosis,only immunomodulato ry and immunosuppressive drugs are recognized as disease-modifying therapies.Howeve r,in recent years,several data from pre-clinical and clinical studies suggested a possible role of physical exe rcise as disease-modifying therapy in multiple sclerosis.Current evidence is sparse and often conflicting,and the mechanisms underlying the neuroprotective and antinflammatory role of exercise in multiple sclerosis have not been fully elucidated.Data,mainly derived from pre-clinical studies,suggest that exe rcise could enhance longterm potentiation and thus neuroplasticity,could reduce neuroinflammation and synaptopathy,and dampen astrogliosis and microgliosis.In humans,most trials focused on direct clinical and MRI outcomes,as investigating synaptic,neuroinflammato ry,and pathological changes is not straightfo rward compared to animal models.The present review analyzed current evidence and limitations in research concerning the potential disease-modifying therapy effects of exercise in multiple sclerosis in animal models and human studies.

Hidden cochlear impairments

Pure tone audiometry is a routine clinical examination used to identify hearing loss. A normal pure tone audiogram is usually taken as evidence of normal hearing. Auditory deficits detected in subjects with normal audiograms, such as poor sound discrimination and auditory perceptual disorders, are generally attributed to central problems. Does the pure tone audiogram truly reflect cochlear status？ Recent evidence suggests that individuals with normal audiogram may still have reduced peripheral auditory responses but normal central responses, indicating that the pure tone audiometry may not detect some types of cochlear injuries. In the cochlea, the outer hair cells （OHCs）, inner hair cells （IHCs）, and the spiral ganglion neurons that synapse with IHCs are the 3 key cochlear components in transducing acoustical vibrations into the neural signals. This report reviews three types of cochlear damage identified in laboratory animals that may not lead to overt hearing loss. The first type of cochlear impairment, such as missing a certain proportion of IHCs without damage to OHCs, may reduce the cochlear output and elevate response threshold; however, the reduced peripheral auditory sensitivity may be restored along the auditory pathway via central gain enhancement. The second type of cochlear impairment, such as selective damage to the synapses of the high-threshold thin auditory nerve fibers （ANFs）, reduces cochlear output at high stimulation levels with no effect on response threshold. In this case the reduced cochlear output may be compensated along the auditory pathway as well. The third type of cochlear impairment, such as missing a certain number of OHCs without damage to others, may not even affect cochlear function at all. These ＂hidden＂ cochlear impairments do not result in overt hearing loss, but they may increase the vulnerability of the cochlea to traumatic exposure and lead to disrupted central auditory processing.

Subclinical hearing loss associated with aging

Objective:Contribute to clarifying the existence of subclinical hearing deficits associated with aging.Design:In this work,we study and compare the auditory perceptual and electrophysiological performance of normal-hearing young and adult subjects(tonal audiometry,high-frequency tone threshold,a triplet of digits in noise,and click-evoked auditory brainstem response).Study sample:45 normal hearing volunteers were evaluated and divided into two groups according to age.27 subjects were included in the“young group”(mean 22.1 years),and 18 subjects(mean 42.22 years)were included in the“adult group.”Results:In the perceptual tests,the adult group presented significantly worse tonal thresholds in the high frequencies(12 and 16 kHz)and worse performance in the digit triplet tests in noise.In the electrophysiological test using the auditory brainstem response technique,the adult group presented significantly lower I and V wave amplitudes and higher V wave latencies at the supra-threshold level.At the threshold level,we observed a significantly higher latency in wave V in the adult group.In addition,in the partial correlation analysis,controlling for the hearing level,we observed a relationship(negative)between age and speech in noise performance and high-frequency thresholds.No significant association was observed between age and the auditory brainstem response.Conclusion:The results are compatible with subclinical hearing loss associated with aging.

Liquid–liquid phase separation in synaptopathies

Liquid–liquid phase separation has emerged as an important mechanism for regulating cell activity by promoting the formation of membrane-less condensates.In the nervous system,the formation of distinct molecular condensates via phase separation is involved in synaptic assembly and function.Disruption of phase separation is associated with several disease states,such as cancer,neurodegenerative disorders,and neurodevelopmental disorders.This review summarizes the function of phase separation in the assembly and plasticity of the synapse,discusses the role of abnormal phase separation in neurological diseases,and proposes potential treatment options for these neurological diseases based on phase separation.

Hidden hearing loss:current perspectives and potential therapies

Hidden hearing loss(HHL),an auditory dysfunction that has gained much recent attention,has the hallmarks of speech discrimination and intelligibility deficits with normal or near-normal hearing thresholds.The pathological mechanisms of HHL are complicated and are not yet fully understood.HHL can be resulted from disorders of the central nervous system such as auditory cortex,and/or pathological changes of inner ear.Thus far,2 pathological phenomena,synaptopathy and auditory nerve demyelination,have been reported as underlying causes of otogenic HHL.Here,we review the clinical and physiological characteristics of HHL as well as the molecular pathological mechanisms of otogenic HHL and aim to allude to potential therapy targets for clinical applications in the future.