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. Our results show that the mutation produces no alteration of RNA but does dramatically decrease maximal and basal PDE6 activity, apparently caused by a decrease in protein stability and transport. The enzymatic properties of the remaining mutant PDE6 appear to be nearly normal. We demonstrate that an increase in free cGMP, which would result from decreased PDE6 activity and serve to increase opening of the cGMP-gated channels and calcium influx, is an underlying cause of cell death: degeneration of rd10/ double mutants is slower than the parent rd10 line. Paradoxically, degeneration in rd10/ is also slower than in This rescue is correlated with a lowering of cGMP content in retinas and suggests that it may be caused by mislocalization of active PDE6. Single-cell recordings from rd10 rods show that the rates of rise and decay of the response are significantly slower; simulations indicate that these changes are primarily the result of the decrease in PDE6 concentration and rod collecting area. Together, these results provide insights into the complex mechanisms that underlie rd10-mediated retinal degeneration and a cautionary note for analysis of therapeutic interventions.

Cochlear implants have been used to restore hearing to more than half a million people around the world. The restored hearing allows most recipients to understand spoken speech without relying on visual cues. While speech comprehension in quiet is generally high for recipients, many complain about the sound of music. The present study examines consonance and dissonance perception in nine cochlear implant users and eight people with no known hearing loss. Participants completed web-based assessments to characterize low-level psychophysical sensitivities to modulation and pitch, as well as higher-level measures of musical pleasantness and speech comprehension in background noise. The underlying hypothesis is that sensitivity to modulation and pitch, in addition to higher levels of musical sophistication, relate to higher-level measures of music and speech perception. This hypothesis tested true with strong correlations observed between measures of modulation and pitch with measures of consonance ratings and speech recognition. Additionally, the cochlear implant users who were the most sensitive to modulations and pitch, and who had higher musical sophistication scores, had similar pleasantness ratings as those with no known hearing loss. The implication is that better coding and focused rehabilitation for modulation and pitch sensitivity will broadly improve perception of music and speech for cochlear implant users.

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Cochlear implant (CI) devices take advantage of the tonotopic organization of the auditory nerve to provide moderate speech recognition. While commercial place-pitch strategies are sufficient for speech comprehension in quiet conditions, CI users struggle to detect multiple, simultaneous sources of pitch. In a polyphonic pitch-trajectory task, two streams (low and high pitch) are presented simultaneously. Participants perform a 1-interval-4-alternative forced-choice procedure to identify which stream changed in pitch and whether it went higher or lower in pitch (low-lower/low-higher/high-lower/high-higher). The low and high streams are high-rate pulsetrains modulated at 110 Hz and 220 Hz, respectively. The stimulus is 1 s in duration and the target stream contains an ascending or descending modulation-frequency sweep over the last 200 ms. The low stream will be presented to the most apical electrode and the high stream presented to electrode separations of 0, 2, 4, and 8. Preliminary results indicate that CI users perform better on the electrode psychophysical tasks than on acoustic variations. Additionally, performance is improved with sharper temporal envelopes. These results suggest that CI users are able to perceive polyphonic pitch and that resolution is limited by how temporal information is conveyed by clinical devices.