Sze Chim Lee

The reduced cochlear output and the failure to adapt the central auditory response causes tinnitus in noise exposed rats.

Tinnitus is proposed to be caused by decreased central input from the cochlea, followed by increased spontaneous and evoked subcortical activity that is interpreted as compensation for increased responsiveness of central auditory circuits. We compared equally noise exposed rats separated into groups with and without tinnitus for differences in brain responsiveness relative to the degree of deafferentation in the periphery. We analyzed (1) the number of CtBP2/RIBEYE-positive particles in ribbon synapses of the inner hair cell (IHC) as a measure for deafferentation; (2) the fine structure of the amplitudes of auditory brainstem responses (ABR) reflecting differences in sound responses following decreased auditory nerve activity and (3) the expression of the activity-regulated gene Arc in the auditory cortex (AC) to identify long-lasting central activity following sensory deprivation. Following moderate trauma, 30% of animals exhibited tinnitus, similar to the tinnitus prevalence among hearing impaired humans. Although both tinnitus and no-tinnitus animals exhibited a reduced ABR wave I amplitude (generated by primary auditory nerve fibers), IHCs ribbon loss and high-frequency hearing impairment was more severe in tinnitus animals, associated with significantly reduced amplitudes of the more centrally generated wave IV and V and less intense staining of Arc mRNA and protein in the AC. The observed severe IHCs ribbon loss, the minimal restoration of ABR wave size, and reduced cortical Arc expression suggest that tinnitus is linked to a failure to adapt central circuits to reduced cochlear input.

Noise-Induced Inner Hair Cell Ribbon Loss Disturbs Central Arc Mobilization: A Novel Molecular Paradigm for Understanding Tinnitus

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.

Autonomous functions of murine thyroid hormone receptor TRα and TRβ in cochlear hair cells.

Thyroid hormone acts on gene transcription by binding to its nuclear receptors TRα1 and TRβ. Whereas global deletion of TRβ causes deafness, global TRα-deficient mice have normal hearing thresholds. Since the individual roles of the two receptors in cochlear hair cells are still unclear, we generated mice with a hair cell-specific mutation of TRα1 or deletion of TRβ using the Cre-loxP system. Hair cell-specific TRβ mutant mice showed normal hearing thresholds but delayed BK channel expression in inner hair cells, slightly stronger outer hair cell function, and slightly reduced amplitudes of auditory brainstem responses. In contrast, hair cell-specific TRα mutant mice showed normal timing of BK channel expression, slightly reduced outer hair cell function, and slightly enhanced amplitudes of auditory brainstem responses. Our data demonstrate that TRβ-related deafness originates outside of hair cells and that TRα and TRβ play opposing, non-redundant roles in hair cells. A role for thyroid hormone receptors in controlling key regulators that shape signal transduction during development is discussed. Thyroid hormone may act through different thyroid hormone receptor activities to permanently alter the sensitivity of auditory neurotransmission.

Loss of auditory sensitivity from inner hair cell synaptopathy can be centrally compensated in the young but not old brain

A dramatic shift in societal demographics will lead to rapid growth in the number of older people with hearing deficits. Poorer performance in suprathreshold speech understanding and temporal processing with age has been previously linked with progressing inner hair cell (IHC) synaptopathy that precedes age-dependent elevation of auditory thresholds. We compared central sound responsiveness after acoustic trauma in young, middle-aged, and older rats. We demonstrate that IHC synaptopathy progresses from middle age onward and hearing threshold becomes elevated from old age onward. Interestingly, middle-aged animals could centrally compensate for the loss of auditory fiber activity through an increase in late auditory brainstem responses (late auditory brainstem response wave) linked to shortening of central response latencies. In contrast, old animals failed to restore central responsiveness, which correlated with reduced temporal resolution in responding to amplitude changes. These findings may suggest that cochlear IHC synaptopathy with age does not necessarily induce temporal auditory coding deficits, as long as the capacity to generate neuronal gain maintains normal sound-induced central amplitudes.

Cochlear NMDA Receptors as a Therapeutic Target of Noise-Induced Tinnitus

Background: Accumulating evidence suggests that tinnitus may occur despite normal auditory sensitivity, probably linked to partial degeneration of the cochlear nerve and damage of the inner hair cell (IHC) synapse. Damage to the IHC synapses and deafferentation may occur even after moderate noise exposure. For both salicylate- and noise-induced tinnitus, aberrant N-methyl-d-aspartate (NMDA) receptor activation and related auditory nerve excitation have been suggested as origin of cochlear tinnitus. Accordingly, NMDA receptor inhibition has been proposed as a pharmacologic approach for treatment of synaptopathic tinnitus. Methods: Round-window application of the NMDA receptor antagonist AM-101 (Esketamine hydrochloride gel; Auris Medical AG, Basel, Switzerland) was tested in an animal model of tinnitus induced by acute traumatic noise. The study included the quantification of IHC ribbon synapses as a correlate for deafferentation as well as the measurement of the auditory brainstem response (ABR) to close-threshold sensation level stimuli as an indication of sound-induced auditory nerve activity. Results: We have shown that AM-101 reduced the trauma-induced loss of IHC ribbons and counteracted the decline of ABR wave I amplitude generated in the cochlea/auditory nerve. Conclusion: Local round-window application of AM-101 may be a promising therapeutic intervention for the treatment of synaptopathic tinnitus.

L-type CaV1.2 deletion in the cochlea but not in the brainstem reduces noise vulnerability: implication for CaV1.2-mediated control of cochlear BDNF expression.

Voltage-gated L-type Ca2+ channels (L-VGCCs) like CaV1.2 are assumed to play a crucial role for controlling release of trophic peptides including brain-derived neurotrophic factor (BDNF). In the inner ear of the adult mouse, besides the well-described L-VGCC CaV1.3, CaV1.2 is also expressed. Due to lethality of constitutive CaV1.2 knock-out mice, the function of this ion channel as well as its putative relationship to BDNF in the auditory system is entirely elusive. We recently described that BDNF plays a differential role for inner hair cell (IHC) vesicles release in normal and traumatized condition. To elucidate a presumptive role of CaV1.2 during this process, two tissue-specific conditional mouse lines were generated. To distinguish the impact of CaV1.2 on the cochlea from that on feedback loops from higher auditory centers CaV1.2 was deleted, in one mouse line, under the Pax2 promoter (CaV1.2Pax2) leading to a deletion in the spiral ganglion neurons, dorsal cochlear nucleus, and inferior colliculus. In the second mouse line, the Egr2 promoter was used for deleting CaV1.2 (CaV1.2Egr2) in auditory brainstem nuclei. In both mouse lines, normal hearing threshold and equal number of IHC release sites were observed. We found a slight reduction of auditory brainstem response wave I amplitudes in the CaV1.2Pax2 mice, but not in the CaV1.2Egr2 mice. After noise exposure, CaV1.2Pax2 mice had less-pronounced hearing loss that correlated with maintenance of ribbons in IHCs and less reduced activity in auditory nerve fibers, as well as in higher brain centers at supra-threshold sound stimulation. As reduced cochlear BDNF mRNA levels were found in CaV1.2Pax2 mice, we suggest that a CaV1.2-dependent step may participate in triggering part of the beneficial and deteriorating effects of cochlear BDNF in intact systems and during noise exposure through a pathway that is independent of CaV1.2 function in efferent circuits.

BDNF in Lower Brain Parts Modifies Auditory Fiber Activity to Gain Fidelity but Increases the Risk for Generation of Central Noise After Injury

For all sensory organs, the establishment of spatial and temporal cortical resolution is assumed to be initiated by the first sensory experience and a BDNF-dependent increase in intracortical inhibition. To address the potential of cortical BDNF for sound processing, we used mice with a conditional deletion of BDNF in which Cre expression was under the control of the Pax2 or TrkC promoter. BDNF deletion profiles between these mice differ in the organ of Corti (BDNFPax2-KO) versus the auditory cortex and hippocampus (BDNFTrkC-KO). We demonstrate that BDNFPax2-KO but not BDNFTrkC-KO mice exhibit reduced sound-evoked suprathreshold ABR waves at the level of the auditory nerve (wave I) and inferior colliculus (IC) (wave IV), indicating that BDNF in lower brain regions but not in the auditory cortex improves sound sensitivity during hearing onset. Extracellular recording of IC neurons of BDNFPax2 mutant mice revealed that the reduced sensitivity of auditory fibers in these mice went hand in hand with elevated thresholds, reduced dynamic range, prolonged latency, and increased inhibitory strength in IC neurons. Reduced parvalbumin-positive contacts were found in the ascending auditory circuit, including the auditory cortex and hippocampus of BDNFPax2-KO, but not of BDNFTrkC-KO mice. Also, BDNFPax2-WT but not BDNFPax2-KO mice did lose basal inhibitory strength in IC neurons after acoustic trauma. These findings suggest that BDNF in the lower parts of the auditory system drives auditory fidelity along the entire ascending pathway up to the cortex by increasing inhibitory strength in behaviorally relevant frequency regions. Fidelity and inhibitory strength can be lost following auditory nerve injury leading to diminished sensory outcome and increased central noise.

Premature mortality among people with severe mental illness — New evidence from linked primary care data

Studies assessing premature mortality in people with severe mental illness (SMI) are usually based in one setting, hospital (secondary care inpatients and/or outpatients) or community (primary care). This may lead to ascertainment bias. This study aimed to estimate standardised mortality ratios (SMRs) for all-cause and cause-specific mortality in people with SMI drawn from linked primary and secondary care populations compared to the general population. SMRs were calculated using the indirect method for a United Kingdom population of almost four million between 2004 and 2013. The all-cause SMR was higher in the cohort identified from secondary care hospital admissions (SMR: 2.9; 95% CI: 2.8-3.0) than from primary care (SMR: 2.2; 95% CI: 2.1-2.3) when compared to the general population. The SMR for the combined cohort was 2.6 (95% CI: 2.5-2.6). Cause specific SMRs in the combined cohort were particularly elevated in those with SMI relative to the general population for ill-defined and unknown causes, suicide, substance abuse, Parkinsons disease, accidents, dementia, infections and respiratory disorders (particularly pneumonia), and Alzheimers disease. Solely hospital admission based studies, which have dominated the literature hitherto, somewhat over-estimate premature mortality in those with SMI. People with SMI are more likely to die by ill-defined and unknown causes, suicide and other less common and often under-reported causes. Comprehensive characterisation of mortality is important to inform policy and practice and to discriminate settings to allow for proportionate interventions to address this health injustice.

Author Correction: Defective Gpsm2/Gα i3 signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome

This corrects the article DOI: 10.1038/ncomms14907.

Premature Mortality among People with Severe Mental Illness – New Evidence from Linked Primary Care Data

IntroductionStudies assessing premature mortality in people with severe mental illness (SMI) are often based in one setting, hospital (secondary care inpatients and/or outpatients) or community (primary care). This may lead to ascertainment bias. Objectives and ApproachThis study aimed to estimate standardised mortality ratios (SMRs) for all-cause and cause-specific mortality in people with SMI drawn from linked primary and secondary care populations compared to the general population. Standardised mortality ratios (SMRs) were calculated using the indirect method for a United Kingdom population of almost four million between 2004-2013. ResultsThe all-cause SMR was higher in the cohort identified from secondary care hospital admissions (SMR: 2.9; 95% CI: 2.8-3.0) than from primary care (SMR: 2.2; 95% CI: 2.1-2.3) when compared to the general population. The SMR for the combined cohort was 2.6 (95% CI: 2.5-2.6). Solely hospital admission based studies may somewhat over-estimate premature mortality in those with SMI. However, there is no doubt this remains a major health inequality. Cause specific SMRs in the combined cohort were particularly elevated in those with SMI relative to the general population for ill-defined and unknown causes, suicide, and substance abuse, as well as a number of other causes. Conclusion/ImplicationsThe ability to combine cohorts electronically from primary and secondary care is more representative of the whole population. Comprehensive characterisation of mortality is important to inform policy and practice and to discriminate settings to allow for proportionate interventions to address this health injustice.