Cortical dysmorphology and reduced cortico-collicular projections in an animal model of autism spectrum disorder.

Autism spectrum disorder is a neurodevelopmental disability that includes sensory disturbances. Hearing is frequently affected and ranges from deafness to hypersensitivity. In utero exposure to the antiepileptic valproic acid is associated with increased risk of autism spectrum disorder in humans and timed valproic acid exposure is a biologically relevant and validated animal model of autism spectrum disorder. Valproic acid-exposed rats have fewer neurons in their auditory brainstem and thalamus, fewer calbindin-positive neurons, reduced ascending projections to the midbrain and thalamus, elevated thresholds, and delayed auditory brainstem responses. Additionally, in the auditory cortex, valproic acid exposure results in abnormal responses, decreased phase-locking, elevated thresholds, and abnormal tonotopic maps. We therefore hypothesized that in utero, valproic acid exposure would result in fewer neurons in auditory cortex, neuronal dysmorphology, fewer calbindin-positive neurons, and reduced connectivity. We approached this hypothesis using morphometric analyses, immunohistochemistry, and retrograde tract tracing. We found thinner cortical layers but no changes in the density of neurons, smaller pyramidal and non-pyramidal neurons in several regions, fewer neurons immunoreactive for calbindin-positive, and fewer cortical neurons projecting to the inferior colliculus. These results support the widespread impact of the auditory system in autism spectrum disorder and valproic acid-exposed animals and emphasize the utility of simple, noninvasive auditory screening for autism spectrum disorder.

Asymmetry in Cortical Thickness of the Heschl's Gyrus in Unilateral Ear Canal Atresia.

HYPOTHESIS: Unilateral congenital conductive hearing impairment in ear canal atresia leads to atrophy of the gray matter of the contralateral primary auditory cortex or changes in asymmetry pattern if left untreated in childhood. BACKGROUND: Unilateral ear canal atresia with associated severe conductive hearing loss results in deteriorated sound localization and difficulties in understanding of speech in a noisy environment. Cortical atrophy in the Heschl's gyrus has been reported in acquired sensorineural hearing loss but has not been studied in unilateral conductive hearing loss. METHODS: We obtained T1w and T2w FLAIR MRI data from 17 subjects with unilateral congenital ear canal atresia and 17 matched controls. Gray matter volume and thickness were measured in the Heschl's gyrus using Freesurfer. RESULTS: In unilateral congenital ear canal atresia, Heschl's gyrus exhibited cortical thickness asymmetry (right thicker than left, corrected p = 0.0012, mean difference 0.25 mm), while controls had symmetric findings. Gray matter volume and total thickness did not differ from controls with normal hearing. CONCLUSION: We observed cortical thickness asymmetry in congenital unilateral ear canal atresia but no evidence of contralateral cortex atrophy. Further research is needed to understand the implications of this asymmetry on central auditory processing deficits.

Functional Brain Regions Linked to Tinnitus Pathology and Compensation During Task Performance: A Systematic Review.

OBJECTIVE: To systematically search the literature and organize relevant advancements in the connection between tinnitus and the activity of different functional brain regions using functional magnetic resonance imaging (fMRI). DATA SOURCES: MEDLINE (OVID), EMBASE (OVID), CINAHL (EBSCO), Web of Science, ProQuest Dissertations & Theses Global, Cochrane Database of Systematic Reviews, and PROSPERO from inception to April 2022. REVIEW METHODS: Studies with adult human subjects who suffer from tinnitus and underwent fMRI to relate specific regions of interest to tinnitus pathology or compensation were included. In addition, fMRI had to be performed with a paradigm of stimuli that would stimulate auditory brain activity. Exclusion criteria included non-English studies, animal studies, and studies that utilized a resting state magnetic resonance imaging or other imaging modalities. RESULTS: The auditory cortex may work to dampen the effects of central gain. Results from different studies show variable changes in the Heschl's gyrus (HG), with some showing increased activity and others showing inhibition and volume loss. After controlling for hyperacusis and other confounders, tinnitus does not seem to influence the inferior colliculus (IC) activation. However, there is decreased connectivity between the auditory cortex and IC. The cochlear nucleus (CN) generally shows increased activation in tinnitus patients. fMRI evidence indicates significant inhibition of thalamic gating. Activating the thalamus may be of important therapeutic potential. CONCLUSION: Patients with tinnitus have significantly altered neuronal firing patterns, especially within the auditory network, when compared to individuals without tinnitus. Tinnitus and hyperacusis commonly coexist, making differentiation of the effects of these 2 phenomena frequently difficult.

Quantification of the Intrinsic T1 and T2 of Heschl's Gyri with MR Fingerprinting.

PURPOSE: The human primary auditory cortex is located in the Heschl's gyrus (HG). To assess the intrinsic MR property in the gray matter of the HG (GM-HG) with T1 and T2 values using a commercially available MR fingerprinting (MRF) technique. METHODS: The subjects were 10 healthy volunteers (with 20 HGs; mean age, 31.5 years old; range, 25-53 years old). Coronal T1 and T2 maps were obtained with commercially available MRF using a 3-Tesla MR system. Two radiologists measured the T1 and T2 values of the GM-HG, the GM in the superior temporal gyrus (GM-STG), and the GM in the middle temporal gyrus (GM-MTG) by drawing a ROI on coronal maps. RESULTS: For both radiologists, the mean T1 and T2 values of the GM-HG were significantly lower than those in the GM-STG or GM-MTG (P < 0.01). The interobserver reliability using the intraclass correlation coefficients (ICC) (2,1) showed strong agreement for the measurement of the T1 and T2 values (ICCs =⃥ 0.80 and 0.78 for T1 and T2 values, respectively). CONCLUSION: The T1 and T2 values on MRF for the GM-HG were lower than those for the GM-STG and GM-MTG, likely reflecting a higher myelin content and iron deposition in the GM-HG. Quantitative measurements using the MRF can clarify cortical properties with high reliability, which may indicate that MRF mapping provides new insights into the structure of the human cortical GM.

Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex.

BACKGROUND: Effective treatment of Alzheimer's disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. OBJECTIVE: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. METHODS: We quantified intracellular and extracellular antibody labelling of Aß42 in 6 regions of the central auditory system from p14 to p150. RESULTS: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aß42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. CONCLUSION: These results suggest that Aß42 accumulation, but not plaques, may impair gap detection.

Evaluating the Efficacy of a Smartphone App for Tinnitus Relief Using Behavioral and Brain Imaging Measures.

PURPOSE: In this exploratory, open-label study, we used behavioral and brain imaging measures to assess the effectiveness of a smartphone application (ReSound Relief app), which aims to help reduce tinnitus-related distress. METHOD: Fourteen participants with a wide range of tinnitus-related symptoms and who were not currently undergoing any external treatment participated. They completed the 6-month study and reported different levels of engagement with the app. RESULTS: Across a range of tinnitus questionnaires, most participants showed either no change or decrease in tinnitus handicap. Resting-state and task-based functional magnetic resonance imaging (fMRI) data were collected at baseline and the end of the study. Resting-state fMRI of 12 participants revealed alterations in interregional connectivity of default mode, salience, emotion, auditory, and visual processing networks at the end of the intervention period compared to baseline. Ratings of affective sounds (as pleasant, neutral, or unpleasant) were assessed using fMRI, and comparison after 6 months of app usage revealed reduced activity in the left superior temporal gyrus (secondary auditory cortex), right superior occipital gyrus, and left posterior cingulate cortex. Our findings were not significant at a false discovery rate level of p < .05. CONCLUSIONS: The reported changes were not significant, possibly due to the small sample size, heterogeneity of the tinnitus handicap among subjects at the start of the project, and the length of the intervention period. Nevertheless, this study underscores the ease of usage of the app and the potential use of brain imaging to assess changes due to a passive, self-administered intervention for individuals with varying levels of tinnitus severity.

A neural signature of regularity in sound is reduced in older adults.

Sensitivity to repetitions in sound amplitude and frequency is crucial for sound perception. As with other aspects of sound processing, sensitivity to such patterns may change with age, and may help explain some age-related changes in hearing such as segregating speech from background sound. We recorded magnetoencephalography to characterize differences in the processing of sound patterns between younger and older adults. We presented tone sequences that either contained a pattern (made of a repeated set of tones) or did not contain a pattern. We show that auditory cortex in older, compared to younger, adults is hyperresponsive to sound onsets, but that sustained neural activity in auditory cortex, indexing the processing of a sound pattern, is reduced. Hence, the sensitivity of neural populations in auditory cortex fundamentally differs between younger and older individuals, overresponding to sound onsets, while underresponding to patterns in sounds. This may help to explain some age-related changes in hearing such as increased sensitivity to distracting sounds and difficulties tracking speech in the presence of other sound.

Cross-modal connectivity effects in age-related hearing loss.

Age-related sensorineural hearing loss (HL) leads to localized brain changes in the primary auditory cortex, long-range functional alterations, and is considered a risk factor for dementia. Nonhuman studies have repeatedly highlighted cross-modal brain plasticity in sensorial brain networks other than those primarily involved in the peripheral damage, thus in this study, the possible cortical alterations associated with HL have been analyzed using a whole-brain multimodal connectomic approach. Fifty-two HL and 30 normal hearing participants were examined in a 3T MRI study along with audiological and neurological assessments. Between-regions functional connectivity and whole-brain probabilistic tractography were calculated in a connectome-based manner and graph theory was used to obtain low-dimensional features for the analysis of brain connectivity at global and local levels. The HL condition was associated with a different functional organization of the visual subnetwork as revealed by a significant increase in global efficiency, density, and clustering coefficient. These functional effects were mirrored by similar (but more subtle) structural effects suggesting that a functional repurposing of visual cortical centers occurs to compensate for age-related loss of hearing abilities.

Correlation of Histomorphometric Changes with Diffusion Tensor Imaging for Evaluation of Blast-Induced Auditory Neurodegeneration in Chinchilla.

In the present study, we have evaluated the blast-induced auditory neurodegeneration in chinchilla by correlating the histomorphometric changes with diffusion tensor imaging. The chinchillas were exposed to single unilateral blast-overpressure (BOP) at ∼172dB peak sound pressure level (SPL) and the pathological changes were compared at 1 week and 1 month after BOP. The functional integrity of the auditory system was assessed by auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE). The axonal integrity was assessed using diffusion tensor imaging at regions of interests (ROIs) of the central auditory neuraxis (CAN) including the cochlear nucleus (CN), inferior colliculus (IC), and auditory cortex (AC). Post-BOP, cyto-architecture metrics such as viable cells, degenerating neurons, and apoptotic cells were quantified at the CAN ROIs using light microscopic studies using cresyl fast violet, hematoxylin and eosin, and modified Crossmon's trichrome stains. We observed mean ABR threshold shifts of 30- and 10-dB SPL at 1 week and 1 month after BOP, respectively. A similar pattern was observed in DPAOE amplitudes shift. In the CAN ROIs, diffusion tensor imaging studies showed a decreased axial diffusivity in CN 1 month after BOP and a decreased mean diffusivity and radial diffusivity at 1 week after BOP. However, morphometric measures such as decreased viable cells and increased degenerating neurons and apoptotic cells were observed at CN, IC, and AC. Specifically, increased degenerating neurons and reduced viable cells were high on the ipsilateral side when compared with the contralateral side. These results indicate that a single blast significantly damages structural and functional integrity at all levels of CAN ROIs.

Altered Heschl's gyrus duplication pattern in first-episode schizophrenia.

BACKGROUND: Reduced gray matter volumes in the superior temporal gyrus and its subregions, such as Heschl's gyrus (HG) and the planum temporale (PT), have been reported in schizophrenia (Sz). However, it remains unclear whether patients exhibit an altered sulcogyral pattern on the superior temporal plane. METHODS: This magnetic resonance imaging study examined the distribution of HG duplication patterns [i.e., single HG, common stem duplication (CSD), or complete posterior duplication (CPD)] and their relationships with clinical variables and gray matter volumes in the HG and PT of 64 first-episode (FE) patients with Sz and 64 healthy controls. RESULTS: The prevalence of duplicated HG patterns was significantly higher and gray matter volumes in the HG and PT of both hemispheres were smaller in FESz patients than in healthy controls. The right CPD pattern in the FESz group was associated with less severe positive symptoms. In the FESz and control groups, CSD and CPD patterns correlated with larger volumes in the HG and PT, respectively. CONCLUSION: The present results revealed an altered HG duplication pattern at the earliest phase of Sz, which may reflect early neurodevelopmental anomalies. However, reduced HG and PT volumes in the FESz were not explained by this sulcogyral pattern only, supporting the complex superior temporal pathology of Sz.

Laser-Induced Apoptosis of Corticothalamic Neurons in Layer VI of Auditory Cortex Impact on Cortical Frequency Processing.

Corticofugal projections outnumber subcortical input projections by far. However, the specific role for signal processing of corticofugal feedback is still less well understood in comparisonto the feedforward projection. Here, we lesioned corticothalamic (CT) neurons in layers V and/or VI of the auditory cortex of Mongolian gerbils by laser-induced photolysis to investigate their contribution to cortical activation patterns. We have used laminar current-source density (CSD) recordings of tone-evoked responses and could show that, particularly, lesion of CT neurons in layer VI affected cortical frequency processing. Specifically, we found a decreased gain of best-frequency input in thalamocortical (TC)-recipient input layers that correlated with the relative lesion of layer VI neurons, but not layer V neurons. Using cortical silencing with the GABA a -agonist muscimol and layer-specific intracortical microstimulation (ICMS), we found that direct activation of infragranular layers recruited a local recurrent cortico-thalamo-cortical loop of synaptic input. This recurrent feedback was also only interrupted when lesioning layer VI neurons, but not cells in layer V. Our study thereby shows distinct roles of these two types of CT neurons suggesting a particular impact of CT feedback from layer VI to affect the local feedforward frequency processing in auditory cortex.

Growth Hormone and the Auditory Pathway: Neuromodulation and Neuroregeneration.

Growth hormone (GH) plays an important role in auditory development during the embryonic stage. Exogenous agents such as sound, noise, drugs or trauma, can induce the release of this hormone to perform a protective function and stimulate other mediators that protect the auditory pathway. In addition, GH deficiency conditions hearing loss or central auditory processing disorders. There are promising animal studies that reflect a possible regenerative role when exogenous GH is used in hearing impairments, demonstrated in in vivo and in vitro studies, and also, even a few studies show beneficial effects in humans presented and substantiated in the main text, although they should not exaggerate the main conclusions.

Abnormal Auditory Processing and Underlying Structural Changes in 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2 DS), one of the highest genetic risk for the development of schizophrenia, offers a unique opportunity to understand neurobiological and functional changes preceding the onset of the psychotic illness. Reduced auditory mismatch negativity response (MMN) has been proposed as a promising index of abnormal sensory processing and brain pathology in schizophrenia. However, the link between the MMN response and its underlying cerebral mechanisms in 22q11.2 DS remains unexamined. We measured auditory-evoked potentials to frequency deviant stimuli with high-density electroencephalogram and volumetric estimates of cortical and thalamic auditory areas with structural T1-weighted magnetic resonance imaging in a sample of 130 individuals, 70 with 22q11.2 DS and 60 age-matched typically developing (TD) individuals. Compared to TD group, the 22q11.2 deletion carriers reveal reduced MMN response and significant changes in topographical maps and decreased gray matter volumes of cortical and subcortical auditory areas, however, without any correlations between MMN alteration and structural changes. Furthermore, exploratory research on the presence of hallucinations (H+\H-) reveals no change in MMN response in 22q11.2DS (H+ and H-) as compared to TD individuals. Nonetheless, we observe bilateral volume reduction of the superior temporal gyrus and left medial geniculate in 22q11.2DSH+ as compared to 22q11.2DSH- and TD participants. These results suggest that the mismatch response might be a promising neurophysiological marker of functional changes within the auditory pathways that might underlie elevated risk for the development of psychotic symptoms.

A role of oligodendrocytes in information processing.

Myelinating oligodendrocytes enable fast propagation of action potentials along the ensheathed axons. In addition, oligodendrocytes play diverse non-canonical roles including axonal metabolic support and activity-dependent myelination. An open question remains whether myelination also contributes to information processing in addition to speeding up conduction velocity. Here, we analyze the role of myelin in auditory information processing using paradigms that are also good predictors of speech understanding in humans. We compare mice with different degrees of dysmyelination using acute multiunit recordings in the auditory cortex, in combination with behavioral readouts. We find complex alterations of neuronal responses that reflect fatigue and temporal acuity deficits. We observe partially discriminable but similar deficits in well myelinated mice in which glial cells cannot fully support axons metabolically. We suggest a model in which myelination contributes to sustained stimulus perception in temporally complex paradigms, with a role of metabolically active oligodendrocytes in cortical information processing.

Improving glucose metabolism in the auditory cortex delays the aging of auditory function of guinea pig.

The glucose homeostasis is essential for brain function, and energy deficiency is a key feature of brain aging. We investigated whether improving glucose metabolism in the auditory cortex can delay the aging of auditory function of guinea pigs with age-related hearing loss (ARHL) by d-galactose. Auditory function was assessed by auditory brainstem response (ABR), glucose metabolism was detected by micro PET/CT, and the proteome were identified in auditory cortex by two-dimensional electrophoresis and matrix assisted laser desorption/ionization mass spectrometry. Glucose metabolism decreased in the auditory cortex of d-galactose group, and improving glucose metabolism can delay the aging of auditory function by upregulating seven metabolism-related proteins including ATP synthase subunit beta, triosephosphate isomerase, creatine kinase U-type, pyruvate dehydrogenase E1 component subunit beta, alpha-enolase, phosphoglycerate kinase, and tubulin beta-2A chain. These results suggest that the decrease of glucose metabolism in the auditory cortex may be an important role in the aging of auditory function, and improving glucose metabolism in the auditory cortex can delay the aging of auditory function of guinea pig with ARHL induced by d-galactose.

The effect and mechanism of 19S proteasome PSMD11/Rpn6 subunit in D-Galactose induced mimetic aging models.

Regulating proteasome activity is a potent therapeutic aspect of age-related hearing loss, which has been proven to protect neurons from age-related damaging. PSMD11, subunit of the 19S proteasome regulatory particle, is known to mainly up-regulate proteasome activity and prolong aging. However, the mechanism of PSMD11 in age-related hearing loss has not been deeply explored. In the present study, we explore the function and mechanism of PSMD11 protecting neurons in d-Galactose (D-Gal) mimetic aging models. Age-related pathologies were detected by Taq-PCR, ABR, Transmission electron microscopy, toluidine blue and ß-galactosidase staining. The relative expressions of the proteins were explored by Western blotting, oxyblot, immunoprecipitation and immunofluorescence. Flow cytometry was used to manifest the oxidative state. We discovered that proteasome activity was impaired with aging, and that ROS and toxic protein accumulated in D-Gal induced aging models. PSMD11 changed with aging, and was associated with the metabolism of proteasome activity in the D-Gal treated models. Moreover, the knockdown or overexpression of PSMD11 was sufficient to change the oxidative state caused by D-Gal. Our results also demonstrated that PSMD11 could bond to AMPKα1/2 in the auditory cortex and PC12 cells, and AMPKα2 but not AMPKα1 was efficient to regulate the function of PSMD11. Deeper insights into the mechanisms of regulating PSMD11 for the anti-aging process are needed, and may offer novel therapeutic methods for central presbycusis.

Maternal Experience-Dependent Cortical Plasticity in Mice Is Circuit- and Stimulus-Specific and Requires MECP2.

The neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2het ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in WT adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2het , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2het also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically relevant behavior.SIGNIFICANCE STATEMENT Rett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in nonmutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning.

Left hemispheric deficit in the sustained neuromagnetic response to periodic click trains in children with ASD.

BACKGROUND: Deficits in perception and production of vocal pitch are often observed in people with autism spectrum disorder (ASD), but the neural basis of these deficits is unknown. In magnetoencephalogram (MEG), spectrally complex periodic sounds trigger two continuous neural responses-the auditory steady state response (ASSR) and the sustained field (SF). It has been shown that the SF in neurotypical individuals is associated with low-level analysis of pitch in the 'pitch processing center' of the Heschl's gyrus. Therefore, alternations in this auditory response may reflect atypical processing of vocal pitch. The SF, however, has never been studied in people with ASD. METHODS: We used MEG and individual brain models to investigate the ASSR and SF evoked by monaural 40 Hz click trains in boys with ASD (N = 35) and neurotypical (NT) boys (N = 35) aged 7-12-years. RESULTS: In agreement with the previous research in adults, the cortical sources of the SF in children were located in the left and right Heschl's gyri, anterolateral to those of the ASSR. In both groups, the SF and ASSR dominated in the right hemisphere and were higher in the hemisphere contralateral to the stimulated ear. The ASSR increased with age in both NT and ASD children and did not differ between the groups. The SF amplitude did not significantly change between the ages of 7 and 12 years. It was moderately attenuated in both hemispheres and was markedly delayed and displaced in the left hemisphere in boys with ASD. The SF delay in participants with ASD was present irrespective of their intelligence level and severity of autism symptoms. LIMITATIONS: We did not test the language abilities of our participants. Therefore, the link between SF and processing of vocal pitch in children with ASD remains speculative. CONCLUSION: Children with ASD demonstrate atypical processing of spectrally complex periodic sound at the level of the core auditory cortex of the left-hemisphere. The observed neural deficit may contribute to speech perception difficulties experienced by children with ASD, including their poor perception and production of linguistic prosody.

Cellular and Widefield Imaging of Sound Frequency Organization in Primary and Higher Order Fields of the Mouse Auditory Cortex.

The mouse auditory cortex (ACtx) contains two core fields-primary auditory cortex (A1) and anterior auditory field (AAF)-arranged in a mirror reversal tonotopic gradient. The best frequency (BF) organization and naming scheme for additional higher order fields remain a matter of debate, as does the correspondence between smoothly varying global tonotopy and heterogeneity in local cellular tuning. Here, we performed chronic widefield and two-photon calcium imaging from the ACtx of awake Thy1-GCaMP6s reporter mice. Data-driven parcellation of widefield maps identified five fields, including a previously unidentified area at the ventral posterior extreme of the ACtx (VPAF) and a tonotopically organized suprarhinal auditory field (SRAF) that extended laterally as far as ectorhinal cortex. Widefield maps were stable over time, where single pixel BFs fluctuated by less than 0.5 octaves throughout a 1-month imaging period. After accounting for neuropil signal and frequency tuning strength, BF organization in neighboring layer 2/3 neurons was intermediate to the heterogeneous salt and pepper organization and the highly precise local organization that have each been described in prior studies. Multiscale imaging data suggest there is no ultrasonic field or secondary auditory cortex in the mouse. Instead, VPAF and a dorsal posterior (DP) field emerged as the strongest candidates for higher order auditory areas.

Hyperbaric Oxygen Treatment Ameliorates Hearing Loss and Auditory Cortex Injury in Noise Exposed Mice by Repressing Local Ceramide Accumulation.

Noise-induced hearing loss (NIHL) relates closely to auditory cortex (AC) injury, so countermeasures aiming at the AC recovery would be of benefit. In this work, the effect of hyperbaric oxygen treatment on NIHL was elucidated, which was imposed on mice before (HBOP), during (HBOD) or after (HBOA) noise exposure. Morphology of neurons was assayed by hematoxylin-eosin or Nissl staining. Ceramide (Cer) level was measured through immunohistochemistry analysis. Apoptotic neurons were counted using transferase-mediated dUTP nick end labeling (TUNEL) staining. We demonstrated that the intense, broad band noise raised the threshold of auditory brainstem response, evoked neuronal degeneration or apoptosis and triggered the Cer accumulation in AC, all of which were restored significantly by HBOP, but not HBOD or HBOA. Cer over-generation reversed the advantages of HBOP significantly, while its curtailment recapitulated the effect. Next, noise exposure raised the superoxide or malondialdehyde (MDA) production which was blocked by HBOP or Cer repression. Oxidative control not only attenuated the hearing loss or neurodegeneration but, in turn, reduced the Cer formation significantly. In summary, mutual regulation between Cer and oxidative stress underlies the HBOP's curative effect on hearing loss and neuronal damage in noise-exposed mice.