Compartmentalized and signal-selective gap junctional coupling in the hearing cochlea

Gap junctional intercellular communication (GJIC) plays a major role in cochlear function. Recent evidence suggests that connexin 26 (Cx26) and Cx30 are the major constituent proteins of cochlear gap junction channels, possibly in a unique heteromeric configuration. We investigated the functional and structural properties of native cochlear gap junctions in rats, from birth to the onset of hearing [ postnatal day 12 (P12)]. Confocal immunofluorescence revealed increasing Cx26 and Cx30 expression from P0 to P12. Functional GJIC was assessed by coinjection of Lucifer yellow (LY) and Neurobiotin (NBN) during whole-cell recordings in cochlear slices. At P0, there was restricted dye transfer between supporting cells around outer hair cells. Transfer was more extensive between supporting cells around inner hair cells. At P8, there was extensive transfer of both dyes between all supporting cell types. By P12, LY no longer transferred between the supporting cells immediately adjacent to hair cells but still transferred between more peripheral cells. NBN transferred freely, but it did not transfer between inner and outer pillar cells. Freeze fracture further demonstrated decreasing GJIC between inner and outer pillar cells around the onset of hearing. These data are supportive of the appearance of signal-selective gap junctions around the onset of hearing, with specific properties required to support auditory function. Furthermore, they suggest that separate medial and lateral buffering compartments exist in the hearing cochlea, which are individually dedicated to the homeostasis of inner hair cells and outer hair cells

Connexins and gap junctions in the inner ear - it's not just about K(+) recycling

Normal development, function and repair of the sensory epithelia in the inner ear are all dependent on gap junctional intercellular communication. Mutations in the connexin genes GJB2 and GJB6 (encoding CX26 and CX30) result in syndromic and non-syndromic deafness via various mechanisms. Clinical vestibular defects, however, are harder to connect with connexin dysfunction. Cx26 and Cx30 proteins are widely expressed in the epithelial and connective tissues of the cochlea, where they may form homomeric or heteromeric gap junction channels in a cell-specific and spatiotemporally complex fashion. Despite the study of mutant channels and animal models for both recessive and dominant autosomal deafness, it is still unclear why gap junctions are essential for auditory function, and why Cx26 and Cx30 do not compensate for each other in vivo. Cx26 appears to be essential for normal development of the auditory sensory epithelium, but may be dispensable during normal hearing. Cx30 appears to be essential for normal repair following sensory cell loss. The specific modes of intercellular signalling mediated by inner ear gap junction channels remain undetermined, but they are hypothesised to play essential roles in the maintenance of ionic and metabolic homeostasis in the inner ear. Recent studies have highlighted involvement of gap junctions in the transfer of essential second messengers between the non-sensory cells, and have proposed roles for hemichannels in normal hearing. Here, we summarise the current knowledge about the molecular and functional properties of inner ear gap junctions, and about tissue pathologies associated with connexin mutations

Restoring the balance: regeneration of hair cells in the vestibular system of the inner ear

Loss of the sensory “hair cells” (HCs) from the vestibular (balance) system of the inner ear results in dizziness and balance dysfunction contributing to falls. In the inner ears of non-mammalian vertebrates, there is spontaneous and complete replacement of lost HCs. The regenerates derive from the non-sensory supporting cells (SCs) that surround each HC either from the daughter cells following SC division or by direct, non-mitotic conversion of SCs. In mammals, there is a very limited capacity to regenerate vestibular HCs but only a small percentage is replaced. They arise exclusively by SC conversion. Recent work in mice, and some in humans, has shown possibilities for inducing SCs to convert to cells expressing some HC characteristics, but that differentiation to fully functional HCs is incomplete. Identification of necessary transcription factors, and/or epigenetic modifiers as well as targets to promote SC proliferation is ongoing

Expanding field education: Hope Trust Community Garden

fals

Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear

Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed bySorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle

The enigmatic root cell - Emerging roles contributing to fluid homeostasis within the cochlear outer sulcus.

Despite their curious morphology prompting numerous hypotheses of their normal function, the root cells lining the cochlear outer sulcus have long evaded physiological characterization. A growing body of evidence now suggests that they regulate the solute content of the endolymph and/or the perilymph, and may be essential in safe-guarding the global homeostasis of the cochlea. Immuno-labeling experiments have demonstrated polarized expression of key ion transport proteins, and recent electrophysiological recordings have identified specific membrane conductances. These studies have painted a clearer picture of how this unusual cell type may contribute to the maintenance of sound transduction, and how they may be central to pathological processes associated with various forms of hearing loss

The influence of smoking, sedentary lifestyle and obesity on cognitive impairment-free life expectancy

BACKGROUND Smoking, sedentary lifestyle and obesity are risk factors for mortality and dementia. However, their impact on cognitive impairment-free life expectancy (CIFLE)has not previously been estimated. METHODS Data were drawn from the DYNOPTA dataset which was derived by harmonizing and pooling common measures from five longitudinal ageing studies. Participants for whom the Mini-Mental State Examination was available were included (N¼8111,48.6% men). Data on education, sex, body mass index, smoking and sedentary lifestyle were collected and mortality data were obtained from Government Records via data linkage.Total life expectancy (LE), CIFLE and years spent with cognitive impairment (CILE)were estimated for each risk factor and total burden of risk factors. RESULTS CILE was approximately 2 years for men and 3 years for women, regardless of age. For men and women respectively, reduced LE associated with smoking was 3.82and 5.88 years, associated with obesity was 0.62 and 1.72 years and associated with being sedentary was 2.50 and 2.89 years. Absence of each risk factor was associated with longer LE and CIFLE, but also longer CILE for smoking in women and being sedentary in both sexes. Compared with participants with no risk factors, those with 2þ had shorter CIFLE of up to 3.5 years depending on gender and education level. CONCLUSIONS Population level reductions in smoking, sedentary lifestyle and obesity increase longevity and number of years lived without cognitive impairment. Years lived with cognitive impairment may also increase.This work was supported by a National Health and Medical Research Council grant # 410215 and by the Australian Research Council Centre of Excellence in Population Ageing Research (CE110001029). K.J.A is funded by NHMRC Fellowship #1002560. C.J. is funded by the AXA Research Fund

Characterizing human vestibular sensory epithelia for experimental studies: new hair bundles on old tissue and implications for therapeutic interventions in ageing.

Balance disequilibrium is a significant contributor to falls in the elderly. The most common cause of balance dysfunction is loss of sensory cells from the vestibular sensory epithelia of the inner ear. However, inaccessibility of inner ear tissue in humans severely restricts possibilities for experimental manipulation to develop therapies to ameliorate this loss. We provide a structural and functional analysis of human vestibular sensory epithelia harvested at trans-labyrinthine surgery. We demonstrate the viability of the tissue and labeling with specific markers of hair cell function and of ion homeostasis in the epithelium. Samples obtained from the oldest patients revealed a significant loss of hair cells across the tissue surface, but we found immature hair bundles present in epithelia harvested from patients >60 years of age. These results suggest that the environment of the human vestibular sensory epithelium could be responsive to stimulation of developmental pathways to enhance hair cell regeneration, as has been demonstrated successfully in the vestibular organs of adult mice

Demographic, health, physical activity, and workplace factors are associated with lower healthy working life expectancy and life expectancy at age 50

\ua9 The Author(s) 2024.Although retirement ages are rising in the United Kingdom and other countries, the average number of years people in England can expect to spend both healthy and work from age 50 (Healthy Working Life Expectancy; HWLE) is less than the number of years to the State Pension age. This study aimed to estimate HWLE with the presence and absence of selected health, socio-demographic, physical activity, and workplace factors relevant to stakeholders focusing on improving work participation. Data from 11,540 adults in the English Longitudinal Study of Ageing were analysed using a continuous time 3-state multi-state model. Age-adjusted hazard rate ratios (aHRR) were estimated for transitions between health and work states associated with individual and combinations of health, socio-demographic, and workplace factors. HWLE from age 50 was 3.3 years fewer on average for people with pain interference (6.54 years with 95% confidence interval [6.07, 7.01]) compared to those without (9.79 [9.50, 10.08]). Osteoarthritis and mental health problems were associated with 2.2 and 2.9 fewer healthy working years respectively (HWLE for people without osteoarthritis: 9.50 years [9.22, 9.79]; HWLE with osteoarthritis: 7.29 years [6.20, 8.39]; HWLE without mental health problems: 9.76 years [9.48, 10.05]; HWLE with mental health problems: 6.87 years [1.58, 12.15]). Obesity and physical inactivity were associated with 0.9 and 2.0 fewer healthy working years respectively (HWLE without obesity: 9.31 years [9.01, 9.62]; HWLE with obesity: 8.44 years [8.02, 8.86]; HWLE without physical inactivity: 9.62 years [9.32, 9.91]; HWLE with physical inactivity: 7.67 years [7.23, 8.12]). Workers without autonomy at work or with inadequate support at work were expected to lose 1.8 and 1.7 years respectively in work with good health from age 50 (HWLE for workers with autonomy: 9.50 years [9.20, 9.79]; HWLE for workers lacking autonomy: 7.67 years [7.22, 8.12]; HWLE for workers with support: 9.52 years [9.22, 9.82]; HWLE for workers with inadequate support: 7.86 years [7.22, 8.12]). This study identified demographic, health, physical activity, and workplace factors associated with lower HWLE and life expectancy at age 50. Identifying the extent of the impact on healthy working life highlights these factors as targets and the potential to mitigate against premature work exit is encouraging to policy-makers seeking to extend working life as well as people with musculoskeletal and mental health conditions and their employers. The HWLE gaps suggest that interventions are needed to promote the health, wellbeing and work outcomes of subpopulations with long-term health conditions