Cochlear implants (CIs) are neuroprosthetic devices that can provide hearing to deaf people1. Despite the benefits offered by CIs, the time taken for hearing to be restored and perceptual accuracy after long-term CI use remain highly variable2,3. CI use is believed to require neuroplasticity in the central auditory system, and differential engagement of neuroplastic mechanisms might contribute to the variability in outcomes4,5,6,7. Despite extensive studies on how CIs activate the auditory system4,8,9,10,11,12, the understanding of CI-related neuroplasticity remains limited. One potent factor enabling plasticity is the neuromodulator noradrenaline from the brainstem locus coeruleus (LC). Here we examine behavioural responses and neural activity in LC and auditory cortex of deafened rats fitted with multi-channel CIs. The rats were trained on a reward-based auditory task, and showed considerable individual differences of learning rates and maximum performance. LC photometry predicted when CI subjects began responding to sounds and longer-term perceptual accuracy. Optogenetic LC stimulation produced faster learning and higher long-term accuracy. Auditory cortical responses to CI stimulation reflected behavioural performance, with enhanced responses to rewarded stimuli and decreased distinction between unrewarded stimuli. Adequate engagement of central neuromodulatory systems is thus a potential clinically relevant target for optimizing neuroprosthetic device use.
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The data that support the findings of this study are further available on Zenodo (https://doi.org/10.5281/zenodo.7226424) or the NYU Data Catalogue (https://datacatalog.med.nyu.edu/dataset/10584). Source data are provided with this paper.
Custom code used in this study is available on Github at https://github.com/ErinGlennon/CI_rat_analysis.git.
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We thank M. Azadpour, N. Capach, I. Carcea, M. Chesler, M. Donegan, P. Gibson, Z. Gironda, A.E. Hight, M. Insanally, J. Kirk, D. Lin, K.A. Martin, O. Mishkit, J. Multani, J. Neukam, J.T. Roland Jr., E. Sagi, D. Sanes, S. Sara, J.K. Scarpa, J. Schiavo, M. Semerkant, I. Shehu, S. Shokat Fadaei, D. Smyth, J. Tranos, C. Treaba, N. Tritsch and S. Waltzman for comments, discussions and technical assistance; Cochlear for technical support; the Genotyping Core Laboratory of NYU Langone Health for help with genotyping transgenic rats; CILcare for cochleogram analysis; the Stanford Neuroscience Gene Vector and Virus Core and the Deisseroth laboratory for AAVDJ-ef1α-DIO-GCaMP6s (Fig. 2 and Extended Data Figs. 6 and 7); C. Schaulsohn for artwork in Figs. 1a, 2a and 3b. This work was funded by a Vilcek Scholar Award (to E.G.); a Howard Hughes Medical Institute Medical Research Fellowship Award (to A.Z.), a Hirschl/Weill-Caulier Career Award (to R.C.F.); and the National Institutes of Health (grant number F30-DC017351 to E.G., T32GM007308 to E.G., R01-DC003937 to M.A.S., and R01-DC012557 to R.C.F.). Partial support was also received from a research contract from Cochlear to J. T. Roland Jr. In vivo imaging was performed under the DART Preclinical Imaging Core partially funded by the NYU Laura and Isaac Perlmutter Cancer Center Support Grant, NIH/NCI P30CA016087. The Center for Advanced Imaging Innovation and Research (CAI2R, www.cai2r.net) at NYU School of Medicine is supported by NIH/NIBIB P41 EB017183.
The authors declare no competing interests.
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Extended data figures and tables
Extended Data Fig. 1 Auditory conditioning on go/no-go task in normal-hearing rats.
a, Normal-hearing behavioral response curves from three example rats that reached training criteria. Arrowhead, target tone was 4 kHz for all animals. Error bars, response rate ± 95% confidence intervals. b, Average initiation rates for final five days of normal-hearing behavioral performance (N = 16 rats). Error bars, mean ± s.e.m. c, Average hits and false positive rates for final five days (N = 16 rats). d, Average behavioral performance (d’) for final five days (N = 16 rats). Error bars, mean±s.e.m. e, Days to d’ ≥ 1.0 (N = 16 rats). Error bars, median±interquartile range.
Extended Data Fig. 2 CI programming.
a, Depiction of center frequencies for individual CI channels. b, Frequency allocation tables used to select tones for behavioral conditioning based on center frequency of channels with different electrode configurations. c, Example electrodograms, showing that only the CI channel for selected center frequency was activated by the tone.
Extended Data Fig. 3 Deafened animals used the CI to perform the auditory task.
a-p, Behavioral performance for all 16 rats from Fig. 1. Each subpanel is a separate animal. Upper left, behavioral response rates across CI channels with the CI turned on (black) or turned off (red). Arrowhead, target tone programmed to activate channel 3 or 4. Error bars, response rate ± 95% confidence interval. Upper right, d’ over days on stage two. Lower left, hit rate over time. Lower right, false positive rate over time. No difference in d’ for rats with 7-8 active channels (N = 8) vs 3 active channels (N = 8) on testing day for implant on vs off (7-8 active channel implant on d’: 1.8 ± 0.2, 3 active channel implant on d’: 1.6 ± 0.2, p = 0.61, unpaired two-tailed t-test; 7-8 active channel implant off d’: 0.0 ± 0.1, 3 active channel implant off d’: −0.1 ± 0.1, p = 0.39)
Extended Data Fig. 4 Behavioral and electrophysiological confirmation of deafness in implanted rats.
a, Hit rates were lower and false positives were higher in rats when the CI was off (N = 16 rats, on vs off, hits: p < 0.0001; false positives: p = 0.02; paired Wilcoxon signed-rank test). b, Initiation rates decreased when the CI was turned off (N = 16 rats, on vs off, p = 0.0002; paired Wilcoxon signed-rank test). c, Hairs cells were lesioned by the deafening process. Representative immunohistochemistry from normal-hearing cochlea from the right ear (‘NH’) and deafened cochlea from the left ear (‘Deafened’) stained with hair cell marker Myo7a. Scale bar, 100 µm. Summary of hair cell counts showed that deafening significantly reduced the number of OHCs (‘NH’, 2746 ± 116 OHCs in normal-hearing animals; ‘Deaf’ 52 ± 46 OHCs in deafened animals; 98.1% loss of OHCs, N = 4, p = 0.0001, Student’s one-tailed paired t-test) and IHCs (‘NH’ 787 ± 34 IHCs; ‘Deaf’ 387 ± 118 IHCs; 50.8% loss of IHCs, N = 4, p = 0.04, Student’s one-tailed paired t-test). d, ABRs were gone both acutely (immediately after deafening) and weeks later. Example waveforms from the same rat with 4 kHz stimuli at 70 dB SPL, 80 dB SPL, and 90 dB SPL; chronic post-deafening ABRs measured 41 days post-deafening. e, EABRs intact both acutely and weeks later. Stimulation was at ECAP threshold. f, Standard deviation (SD) of acoustically-evoked ABRs (solid lines) and baseline noise (dashed lines) across frequencies from sample rat displayed in d,e. Red, acute deafness; blue, chronic deafness 41 days later. g, Summary of ABR/EABR recordings with stimuli of 4 kHz at 90 dB SPL or ECAP threshold in 14 rats pre- and post-deafening (6 pre and acute post; 4 chronic post; 4 pre, acute, and chronic post). ABRs were equivalent to baseline noise after deafening (‘Pre’, before deafening noise SD: 1.1 ± 0.2 µV, before deafening ABR SD: 3.2 ± 0.3 µV, N = 10, p = 0.0003,; ‘Acute’ just after deafening noise SD: 1.2 ± 0.1 µV, just after deafening ABR SD: 1.2 ± 0.3 µV, N = 10, p = 0.61; ‘Chronic’ weeks after deafening noise SD: 1.6 ± 0.2 µV, weeks after deafening ABR SD: 1.6 ± 0.1 µV, N = 8, p = 0.55; Student’s paired two-tailed t-tests). EABRs were significantly evoked (‘Acute’ just after deafening noise SD: 1.0 ± 0.1 µV, just after deafening EABR SD: 3.9 ± 0.7 µV, N = 10, p = 0.001; ‘Chronic’ weeks after deafening noise SD: 1.2 ± 0.1 µV, weeks after deafening EABR SD: 4.6 ± 0.8 µV, N = 8, p = 0.002, Student’s paired two-tailed t-test). Chronic measurements made between 13–42 days after deafening. h-k, Behavioral performance of four animals from g showing behavioral responses ± 95% confidence interval and d’ values post-deafening on stage 2 when CI is on (black) vs off (red) (upper left), d’ over time (upper right), hit rates and false positive over time (middle), and sample ABR and EABR traces (bottom). *, p < 0.05; **, p < 0.01
Extended Data Fig. 5 Individual variability with CI use was related to false positive rate but not insertion depth, impedance, ECAP thresholds, hit rates, or normal-hearing performance.
a, Example x-rays of full insertion (8 channels) and partial insertion (4–7 channels). b, Days to d’ ≥ 1.0 did not differ based on CI insertion depth (full insertion: N = 9 rats vs partial insertion: N = 7 rats, p = 0.32, unpaired two-tailed Mann–Whitney test). Error bars, median±interquartile range. c, Average impedance of active CI channels over time. Grey dashed lines, individual rats (N = 16). Black, mean±s.e.m. d, Days to d’ ≥ 1.0 did not correlate with initial impedance values (N = 16 rats, Pearson’s r: 0.23, p = 0.40). e, Days to d’ ≥ 1.0 did not correlate with ECAP threshold (N = 16 rats, Pearson’s r: −0.21, p = 0.44). f, CI learning days to d’≥1.0 did not correlate normal-hearing learning days to d’ ≥ 1.0 (N = 16 rats, Pearson’s r: 0.07, p = 0.79). g, Days to d’ ≥ 1.0 did not correlate with hit rate (N = 16 rats, Pearson’s r: 0.16, p = 0.56). h, Days to d’ ≥ 1.0 correlated with false positives (N = 16 rats, Pearson’s r: 0.61, p = 0.01). i, During normal-hearing training, days to d’ ≥ 1.0 did not correlate with maximum d’ performance (N = 16 rats, Pearson’s r: −0.37, p = 0.16). j, Hit rates on first CI day were uncorrelated with hit rates on last normal-hearing day (N = 16 rats, Pearson’s r: 0.02, p = 0.93). k, False positive rates on first CI day were uncorrelated with hit rates on last normal-hearing day (N = 16 rats, Pearson’s r: 0.03, p = 0.90). l, d’ values on first CI day were uncorrelated with hit rates on last normal-hearing day (N = 16 rats, Pearson’s r: −0.03, p = 0.92)
Extended Data Fig. 6 Fiber photometry miss/withhold analysis.
a, Example LC activity aligned to tone onset during stage one CI training on miss trials, showing dF/F in high-miss rate behavioral session 1 (top) and in later low-miss behavioral session 5 (bottom). Error bars, mean ±s.e.m. b, In stage one, LC dF/F signals during miss trials were highest in sessions where the miss rates were highest (N = 4 rats, n = 21 sessions, Pearson’s r: 0.61, p = 0.003). c, LC signals were not predictive of false positive trials in stage two (tone-aligned: N = 4 rats, n = 39 sessions, Pearson’s r: −0.03, p = 0.83; response-aligned: N = 4 rats, n = 38 sessions, Pearson’s r: −0.30, p = 0.06). d, Example LC activity aligned to tone onset during stage two (foil and target training). Miss and withhold trials in high-false positive (F+) behavioral session 2 (top); miss and withhold trials in low-F+ behavioral session 12 (bottom). Error bars, mean ±s.e.m. e, Tone-aligned normalized dF/F LC signals during miss trials over all stage two sessions (N = 4 rats, n = 36 sessions, Pearson’s r: −0.01, p = 0.97). f, Tone-aligned normalized dF/F LC signals during withhold trials over all sessions (N = 4 rats, n = 40 sessions, Pearson’s r: 0.24, p = 0.14)
Extended Data Fig. 7 LC activity in normal-hearing reversal learning.
a, Schematic of go/no-go auditory behavioral task in normal-hearing rats when target tone is changed to a different frequency. After training to response to one target tone (black) while withholding from foil tones (green/red), one of the previously unrewarded tones (green) became the rewarded tone and the previously rewarded tone (black) became unrewarded. b, Example of animal performance on this task to first and second rewarded tones. Black arrowhead, first rewarded tone; green arrowhead, second rewarded tone. Error bars, response rates ± 95% confidence intervals. c, Tone-aligned LC activity, response-aligned LC activity, and miss rates across behavioral sessions in an example animal. Black, miss rates. Green, dF/F responses either tone-aligned (filled symbols, solid lines) or behavioral response-aligned (open symbols, dashed lines). d, Miss rates across all sessions were not correlated with tone-aligned normalized LC dF/F (N = 2 rats, n = 23 behavioral sessions, Pearson’s r: −0.05, p = 0.8). e, Miss rates across all sessions were correlated with dF/F when aligned to behavioral response (N = 2 rats, n = 23 behavioral sessions, Pearson’s r: 0.45, p = 0.03). f, Tone-aligned LC activity, response-aligned LC activity, and false positive rates across behavioral sessions in an example animal. Black, false positives. Green, dF/F responses either tone-aligned (filled symbols, solid lines) or behavioral response-aligned (open symbols, dashed lines). G, False positive rates across all sessions were not correlated with tone-aligned normalized LC dF/F (N = 2 rats, n = 23 behavioral sessions, Pearson’s r: −0.34, p = 0.1). h, False positive rates across all sessions were negatively correlated with dF/F when aligned to behavioral response (N = 2 rats, n = 23 sessions, Pearson’s r: −0.45, p = 0.03). i, Tone-aligned LC activity, response-aligned LC activity, and d’ across behavioral sessions in an example animal. Black, d’. Green, dF/F responses either tone-aligned (filled symbols, solid lines) or behavioral response-aligned (open symbols, dashed lines). j, d’ across all sessions correlated with tone-aligned normalized LC dF/F (N = 2 rats, n = 23 behavioral sessions, Pearson’s r: 0.52, p = 0.01). k, d’ across all sessions was not correlated with dF/F when aligned to behavioral response (N = 2 rats, n = 23 behavioral sessions, Pearson’s r: −0.11, p = 0.6)
Extended Data Fig. 8 LC targeting and behavioral comparison between sham-paired YFP-injected animals vs fiber-mistargeted animals.
a, Surgical approach for targeting LC. Multi-unit recordings were conducted to locate LC and then viral injection and optic fiber placement were based on these coordinates. b, Example LC multi-unit activity evoked by toe pinch. c, Optical fiber placement based on histology and μ-CT/ μ-MRI co-registration. Top, fiber placement in LC-paired animals. Bottom, fiber placement in sham-paired animals (red, mis-targeted fibers outside of LC; black, YFP-injected controls). Scale bar, 1 mm. d, In fiber mis-targeted animals, there was no significant correlation between distance of probe tip for optical stimulation and days to d’ ≥ 1.0 (N = 11 rats, Pearson’s r: 0.17, p = 0.63) e, In fiber mis-targeted animals with at least six days of CI training, there was no significant correlation between distance of probe tip for optical stimulation and maximum performance with CI (N = 10 rats, Pearson’s r: −0.02, p = 0.95). f, Days to d’ ≥ 1.0 was similar between the two sub-groups of sham-paired animals with either YFP-only expression in LC or when fiber was mis-targeted outside LC (YFP: N = 5 rats, mis-targeted: N = 11 rats, p = 0.38, unpaired two-tailed Mann–Whitney test). Error bars, median±interquartile range. g, Sham-paired animals in each subgroup with at least six days of CI training had similar maximum d’ (YFP: N = 4 rats vs mis-targeted: N = 10 rats, p = 0.71, unpaired two-tailed Student’s t-test). h, CI performance (d’) over time in YFP: N = 5 rats vs mis-targeted: N = 11 rats. One YFP animal in f,h and one mis-targeted animal shown in d,f,h did not reach the six-day requirement for maximum performance analysis; these animals are not displayed in e,g. i, Hit rates over time in YFP: N = 5 rats vs mis-targeted: N = 11 rats. j, False positives over time in YFP: N = 5 rats vs mis-targeted: N = 11 rats. Data are mean±s.e.m. except in f. One YFP rat and one mis-targeted rat did not reach the six day performance requirement to calculate maximum d’. This mis-targeted animal is displayed in d, but excluded from e, and both are displayed in f, but excluded from g
Extended Data Fig. 9 LC-paired vs sham-paired animals had comparable CI insertions, impedances, ECAPs, behavioral initiation rates, and lack of residual hearing.
a, Number of intracochlear electrodes as assessed by x-ray was similar between LC-paired rats and sham-paired rats (LC-paired, N = 8 rats vs sham-paired, N = 16 rats, p = 0.93, unpaired two-tailed Mann–Whitney test). Blue, LC-paired animals. Black, sham-paired animals. Error bars, median±interquartile range. b, Degree of insertion did not predict performance across sham-paired (black) and LC-paired (blue) rats (full insertion: 8-channels, N = 14 rats vs partial insertion:4–7 channels, N = 10 rats, p = 0.36, unpaired two-tailed Mann–Whitney test). Measure of center, median. C, No significant correlation between estimated frequency mismatch and learning rate in both sham-paired (black, N = 16 rats, Pearson’s r: 0.39, p = 0.1) and LC-paired (blue, N = 8 rats, Pearson’s r: −0.37, p = 0.4) animals. Two LC-paired animals self-explanted their CIs prior to x-ray assessment of insertion; these animals are not displayed in a,b,c. d, Average impedances of CI channels over time in LC-paired (blue, N = 10) and sham-paired rats (black, N = 16). Dashed lines, individual rats. Solid lines, mean±s.e.m. e, Initial and final impedance values were similar in LC-paired and sham-paired rats (LC-paired: N = 10 rats vs sham-paired: N = 16 rats, initial: p = 0.32; final: p = 0.27; unpaired two-tailed Student’s t-test). f, ECAP thresholds during stage one and stage two training did not differ between LC-paired and sham-paired rats (LC-paired: N = 10 rats vs sham-paired: N = 16 rats, stage one: p = 0.91; stage two: p = 0.64; unpaired two-tailed Student’s t-test). g, Initiation rates were similar between LC-paired and sham-paired rats (LC-paired: N = 10 rats vs sham-paired: N = 16 rats, p = 0.35; unpaired two-tailed Student’s t-test). h, Learning rates with CIs (days to d’ ≥ 1) were not significantly correlated with initiation rates across LC-paired (blue, N = 10 rats, Pearson’s r: −0.49, p = 0.2) or sham-paired rats (black, N = 16 rats, Pearson’s r: −0.23, p = 0.4). i, Behavioral response rates were comparable in sham-paired (N = 16 rats) vs LC-paired (N = 10 rats) animals for sessions when the CI was turned off. (Blue, LC-paired: N = 10 rats vs black, sham-paired: N = 16 rats, hit rate: p = 0.72; false positives: p = 0.61; unpaired two-tailed Student’s t-test). j, d’ values were ~0 for both sham-paired (black, N = 16 rats) and LC-paired (blue, N = 10 rats) animals when the CI was turned off (p = 0.84; unpaired two-tailed Student’s t-test). Animals with high hit rates in I tended to also have high false positive rates; similarly, animals with low hit rates tended to have low false positive rates. k-m, Relating performance before and after deafening on CI performance vs acoustic normal-hearing (NH) task for last NH day vs first CI day in LC-paired animals. No significant correlation between hit rates (N = 10 rats, Pearson’s r: −0.05, p = 0.9) (k), false positives (N = 10 rats, Pearson’s r: −0.26, p = 0.5) (l), or d’ (N = 10 rats, Pearson’s r: −0.27, p = 0.4) (m). Data are error bars, mean±s.e.m. except in a, b
Extended Data Fig. 10 Electrophysiological recordings from the auditory periphery and auditory cortex of implanted rats.
a, Example ECAPs in CN VIII from an LC-paired rat (left), a sham-paired rat (middle), and an untrained rat (right). b, Average ECAP amplitudes (P1-N1) were similar across groups and target/foil channels (LC-paired target ECAP amplitude: 120.0 ± 5.8 µV, LC-paired foil: 94.0 ± 5.2 µV, N = 4 rats; sham-paired target: 124.9 ± 19.6 µV, sham-paired foil: 111.9 ± 16.8 µV, N = 8 rats; untrained: 114.5 ± 3.9 µV, N = 4 rats). There was no significant difference between LC-paired, sham-paired, and untrained animal ECAPs (comparing LC-paired target vs foil, p = 0.27; sham-paired target vs foil, p = 0.55; LC-paired vs sham-paired target, p = 0.59; LC-paired vs sham-paired foil, p = 0.99; untrained vs LC-paired target, p = 0.99; untrained vs LC-paired foil, p = 0.61; untrained vs sham-paired target, p = 0.92; untrained vs sham-paired foil, p = 0.41; two-way ANOVA across all groups with Tukey’s multiple comparisons correction). c, Relative fraction of unresponsive multi-unit sites was greater in untrained vs trained rats (fraction of unresponsive sites in: untrained rat auditory cortex, N = 4 rats, 21.3 ± 10.1% vs trained rat auditory cortex, N = 12 rats 5.5 ± 2.1%, p = 0.03, Student’s unpaired two-tailed t-test). Total number of sites recorded from was comparable in untrained rats (18.5 ± 1.0 sites/animal, N = 4 rats), LC-paired trained rats (17.5 ± 2.8 sites/animal, N = 4 rats), and sham-paired trained rats (20.0 ± 2.4 sites/animal, N = 8 rats). d, Neural vs behavioral d’ values across animals as in Fig. 4h, but with neural d’ values computed using only sites tuned to the target channel (N = 12 rats, Pearson’s r: 0.36, p = 0.25). e, As d, but using only sites where foils were the best channel (N = 12 rats, Pearson’s r: 0.85, p = 0.0005)
This file contains the Supplementary Discussion, Supplementary Table 1 and Supplementary References.
Supplementary Video 1
Example of a deaf rat using CI to respond to presentation of target tones but not foil tones.
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Glennon, E., Valtcheva, S., Zhu, A. et al. Locus coeruleus activity improves cochlear implant performance. Nature 613, 317–323 (2023). https://doi.org/10.1038/s41586-022-05554-8
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