Efficacy of Hearing Aids in Patients with Hearing Difficulties in Noise: Focus on Hidden Hearing Loss.

Hearing aids (HAs) have been used for standard high-frequency hearing loss and tinnitus, but their effects on speech intelligibility in noise (SIN) in people with normal hearing, including hidden hearing loss (HHL), have been little explored. We included in a prospective cohort study patients who experience poor SIN and have normal pure tone average in quiet conditions or slight HL. We used open-fit HAs.

Evolution of rod bipolar cells and rod vision.

Bipolar cells are vertebrate retinal interneurons conveying signals from rod and cone photoreceptors to amacrine and ganglion cells. Bipolar cells are found in all vertebrates and have many structural and molecular affinities with photoreceptors; they probably appeared very early during vertebrate evolution in conjunction with rod and cone progenitors. There are two types of bipolar cells, responding to central illumination with depolarization (ON) or hyperpolarization (OFF).

Molecular characterization of the sea lamprey retina illuminates the evolutionary origin of retinal cell types.

The lamprey, a primitive jawless vertebrate whose ancestors diverged from all other vertebrates over 500 million years ago, offers a unique window into the ancient formation of the retina. Using single-cell RNA-sequencing, we characterize retinal cell types in the lamprey and compare them to those in mouse, chicken, and zebrafish. We find six cell classes and 74 distinct cell types, many shared with other vertebrate species.

RDH12 allows cone photoreceptors to regenerate opsin visual pigments from a chromophore precursor to escape competition with rods.

Capture of a photon by an opsin visual pigment isomerizes its 11-cis-retinaldehyde (11cRAL) chromophore to all-trans-retinaldehyde (atRAL), which subsequently dissociates. To restore light sensitivity, the unliganded apo-opsin combines with another 11cRAL to make a new visual pigment. Two enzyme pathways supply chromophore to photoreceptors.

Genetic manipulation of rod-cone differences in mouse retina.

Though rod and cone photoreceptors use similar phototransduction mechanisms, previous model calculations have indicated that the most important differences in their light responses are likely to be differences in amplification of the G-protein cascade, different decay rates of phosphodiesterase (PDE) and pigment phosphorylation, and different rates of turnover of cGMP in darkness. To test this hypothesis, we constructed TrUx;GapOx rods by crossing mice with decreased transduction gain from decreased transducin expression, with mice displaying an increased rate of PDE decay from increased expression of GTPase-activating proteins (GAPs). These two manipulations brought the sensitivity of TrUx;GapOx rods to within a factor of 2 of WT cone sensitivity, after correcting for outer-segment dimensions.

A Novel Role for UNC119 as an Enhancer of Synaptic Transmission.

Mammalian UNC119 is a ciliary trafficking chaperone highly expressed in the inner segment of retinal photoreceptors. Previous research has shown that UNC119 can bind to transducin, the synaptic ribbon protein RIBEYE, and the calcium-binding protein CaBP4, suggesting that UNC119 may have a role in synaptic transmission. We made patch-clamp recordings from retinal slices in mice with the gene deleted and showed that removal of even one gene of has no effect on the rod outer segment photocurrent, but acted on bipolar cells much like background light: it depolarized membrane potential, decreased sensitivity, accelerated response decay, and decreased the Hill coefficient of the response-intensity relationship.

Cones and cone pathways remain functional in advanced retinal degeneration.

Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment.

Vision: Life on the dark side.

Mice detect decreases in illumination in dim light near the visual threshold with OFF retinal ganglion cells.

A hyperpolarizing rod bipolar cell in the sea lamprey, Petromyzon marinus.

Retinal bipolar cells receive direct input from rod and cone photoreceptors and send axons into the inner retina, synapsing onto amacrine and ganglion cells. Bipolar cell responses can be either depolarizing (ON) or hyperpolarizing (OFF); in lower vertebrates, bipolar cells receive mixed rod and cone input, whereas in mammals, input is mostly segregated into 14 classes of cone ON and OFF cells and a single rod ON bipolar cell. We show that lamprey, like mammals, have rod bipolar cells with little or no cone input, but these cells are OFF rather than ON.

Reproducibility of the Rod Photoreceptor Response Depends Critically on the Concentration of the Phosphodiesterase Effector Enzyme.

The high sensitivity of night vision requires that rod photoreceptors reliably and reproducibly signal the absorption of single photons, a process that depends on tight regulation of intracellular cGMP concentration through the phototransduction cascade. Here in the mouse (Mus musculus), we studied a single-site mutation of the gene for the α subunit of rod photoreceptor phosphodiesterase (PDEA), made with the aim of removing a noncatalytic binding site for cGMP. This mutation unexpectedly eliminated nearly all PDEA expression and reduced expression of the β subunit (PDEB) to ∼5%-10% of WT.

Analysis of waveform and amplitude of mouse rod and cone flash responses.

Key Points: Most vertebrate eyes have rod and cone photoreceptors, which use a signal transduction pathway consisting of many biological processes to transform light into an electrical response. We dissect and quantify the contribution of each of these processes to the photoreceptor light response by using a novel method of analysis that provides an analytical solution for the entire time course of the dim-flash light response. We find that the shape of the light response is exclusively controlled by deactivation parameters.

Light responses of mammalian cones.

Cone photoreceptors provide the foundation of most of human visual experience, but because they are smaller and less numerous than rods in most mammalian retinas, much less is known about their physiology. We describe new techniques and approaches which are helping to provide a better understanding of cone function. We focus on several outstanding issues, including the identification of the features of the phototransduction cascade that are responsible for the more rapid kinetics and decreased sensitivity of the cone response, the roles of inner-segment voltage-gated and Ca-activated channels, the means by which cones remain responsive even in the brightest illumination, mechanisms of cone visual pigment regeneration in constant light, and energy consumption of cones in comparison to that of rods.

Rod Photoreceptors Avoid Saturation in Bright Light by the Movement of the G Protein Transducin.

Rod photoreceptors can be saturated by exposure to bright background light, so that no flash superimposed on the background can elicit a detectable response. This phenomenon, called increment saturation, was first demonstrated psychophysically by Aguilar and Stiles and has since been shown in many studies to occur in single rods. Recent experiments indicate, however, that rods may be able to avoid saturation under some conditions of illumination.

Pupillary light reflex of lamprey Petromyzon marinus.

The discoveries of the photopigment melanopsin and intrinsically photosensitive retinal ganglion cells (ipRGCs) have revealed novel mechanisms of light detection now known to control several kinds of non-image-forming vision, including regulation of mood, the circadian rhythm, and the pupillary light reflex (PLR). These remarkable discoveries have been made mostly on mammals, but many vertebrates express melanopsin and adjust the diameter of the pupil to the ambient light intensity to extend the operating range of vision and reduce spherical aberration. We were curious to know whether a PLR controlled by melanopsin is also present in lamprey, which are members of the only remaining group of jawless vertebrates (agnathans) which diverged from all other vertebrates about 500 million years ago.

Elevated energy requirement of cone photoreceptors.

We have used recent measurements of mammalian cone light responses and voltage-gated currents to calculate cone ATP utilization and compare it to that of rods. The largest expenditure of ATP results from ion transport, particularly from removal of Na entering outer segment light-dependent channels and inner segment hyperpolarization-activated cyclic nucleotide-gated channels, and from ATP-dependent pumping of Ca entering voltage-gated channels at the synaptic terminal. Single cones expend nearly twice as much energy as single rods in darkness, largely because they make more synapses with second-order retinal cells and thus must extrude more Ca In daylight, cone ATP utilization per cell remains high because cones never remain saturated and must continue to export Na and synaptic Ca even in bright illumination.

A kinetic analysis of mouse rod and cone photoreceptor responses.

Key Points: Most vertebrate eyes have rods for dim-light vision and cones for brighter light and higher temporal sensitivity. Rods evolved from cone-like precursors through expression of different transduction genes or the same genes at different expression levels, but we do not know which molecular differences were most important. We approached this problem by analysing rod and cone responses with the same model but with different values for model parameters.

Separate ON and OFF pathways in vertebrate vision first arose during the Cambrian.

Ellis et al. show that retinal ON and OFF bipolar cells, and the novel metabotropic glutamate receptors of ON bipolar-cell dendrites, are both present in lamprey. They conclude that the fundamental organizing principle of separate ON and OFF pathways first appeared in the vertebrate visual system over 500 million years ago in the late Cambrian.

Diminished Cone Sensitivity in cpfl3 Mice Is Caused by Defective Transducin Signaling.

Purpose: Cone photoreceptor function loss 3 (Gnat2cpfl3/cpfl3 or cpfl3) is a mouse model commonly used as a functional cones null from a naturally occurring mutation in the α-subunit of cone transducin (Gnat2). We nevertheless detected robust cone-mediated light responses from cpfl3 animals, which we now explore.

Methods: Recordings were made from whole retina and from identified cones with whole-cell patch clamp in retinal slices.

Membrane conductances of mouse cone photoreceptors.

Vertebrate photoreceptor cells respond to light through a closure of CNG channels located in the outer segment. Multiple voltage-sensitive channels in the photoreceptor inner segment serve to transform and transmit the light-induced outer-segment current response. Despite extensive studies in lower vertebrates, we do not know how these channels produce the photoresponse of mammalian photoreceptors.

Lamprey vision: Photoreceptors and organization of the retina.

The lamprey is an important non-model vertebrate because it is an agnathan or jawless vertebrate and belongs to the superclass cyclostomata, a group that split off from the rest of the vertebrates 500 million years ago. Investigation of the lamprey retina may therefore reveal attributes of visual function that were characteristic of even the most primitive vertebrates. The rod and cone photoreceptors are a striking example, because the biochemistry and physiology of phototransduction is remarkably similar between lamprey and the rest of the vertebrates, including mammals.

Voltage-clamp recordings of light responses from wild-type and mutant mouse cone photoreceptors.

We describe the first extensive study of voltage-clamp current responses of cone photoreceptors in unlabeled, dark-adapted mouse retina using only the position and appearance of cone somata as a guide. Identification was confirmed from morphology after dye filling. Photocurrents recorded from wild-type mouse cones were biphasic with a fast cone component and a slower rod component.

Light-Driven Regeneration of Cone Visual Pigments through a Mechanism Involving RGR Opsin in Müller Glial Cells.

While rods in the mammalian retina regenerate rhodopsin through a well-characterized pathway in cells of the retinal pigment epithelium (RPE), cone visual pigments are thought to regenerate in part through an additional pathway in Müller cells of the neural retina. The proteins comprising this intrinsic retinal visual cycle are unknown. Here, we show that RGR opsin and retinol dehydrogenase-10 (Rdh10) convert all-trans-retinol to 11-cis-retinol during exposure to visible light.

The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx.

The retinal degeneration model rd10 contains a missense mutation of the catalytic PDE6 β subunit, which hydrolyzes cGMP in response to light. This model produces cell death more slowly than others caused by PDE6 loss of function, making it of particular interest for studying potential therapeutics. We used morphology, biochemistry, and single-cell physiology to examine the mechanism of rd10 degeneration.