The enduring plasticity of the adult brain supports a remarkable recovery of perceptual and motor capabilities following peripheral nerve injury. In sensory cortex, reorganization following injury involves a rapid unmasking of inputs from adjacent, undamaged regions of the sensory periphery and, in cases of incomplete injury, a slower, progressive increase in responsiveness to surviving nerve fibers within the damaged region (Rasmusson, 1982; Merzenich et al., 1983; Gilbert and Wiesel, 1992; Kaas et al., 1990; Robertson and Irvine, 1989; Qiu et al., 2000; Chambers et al., 2016; Calford and Tweedale, 1988). The initial stages of this reorganization may be enabled by homeostatic processes that compensate for dramatic swings in afferent input to maintain neural excitability around a set point (Nahmani and Turrigiano, 2014). Recordings from cortical pyramidal neurons in culture or acute brain slices following sudden shifts in excitatory input have revealed a coordinated sequence of changes at glutamatergic and GABAergic synapses that normalize firing rates and rebalance network activity (Kilman et al., 2002; O'Brien et al., 1998; Turrigiano et al., 1998; Xue et al., 2014; D'amour and Froemke, 2015; Li et al., 2014). Whether and how synaptic and extra-synaptic modifications underlie reorganized sensory processing in deafferented zones of the adult cortex remains to be determined, but accumulating evidence from intact preparations suggests that the stabilization of new synaptic inputs from spared regions of the sensory periphery may emerge through a combination of rapid disinhibition and increased structural motility (Li et al., 2014; Marik et al., 2014; Yamahachi et al., 2009; Darian-Smith and Gilbert, 1994; Keck et al., 2011, 2013; Garraghty et al., 1991; Florence et al., 1998).

In the auditory system, a loss of cochlear hair cells and/or cochlear nerve afferent synapses is associated with reduced GABA signaling and cortical hyperexcitability, as manifest in elevated spontaneous firing rates, enhanced central gain and unmasking of sound-evoked responses from undamaged regions of the cochlea (Qiu et al., 2000; Chambers et al., 2016; Seki and Eggermont, 2003; Yang et al., 2012; Scholl and Wehr, 2008). However, these biomarkers have not been compared with one another over the full course of functional recovery with fine-grain temporal resolution at the level of individual neurons. As a result, it is unclear whether dynamic changes in intracortical inhibition precede, follow, outlast or recede ahead of functional changes in receptive field mapping and neural hyperexcitability. Nor is it clear whether the decline in GABA markers following peripheral injury arise from a reduced influence of PV-expressing fast-spiking interneurons, which synapse onto pyramidal neuron somata and have a well-recognized role in gating activity-dependent cortical plasticity, or instead from other GABA neuron subtypes, which can synapse onto other GABA neurons and exert a net excitatory effect on network activity (Isaacson and Scanziani, 2011). Here, we address these unanswered questions by measuring changes in PV-mediated intracortical inhibition alongside hyperexcitability and receptive field plasticity from individual regular spiking (RS) putative pyramidal neurons over a several month period surrounding varying degrees of auditory nerve damage. These findings highlight a rapid loss and recovery in PV-mediated inhibition that may compensate for a sudden drop in afferent drive following cochlear afferent loss to support a progressive recovery of sensory processing from spared nerve fibers.

We implanted optetrode assemblies into the primary auditory cortex (A1) of adult PV-Cre:Ai32 mice (Figure 1a) to isolate regular spiking (RS) putative pyramidal neurons based on their spike shape and estimate the strength of local inhibition on RS units during optogenetic activation of PV–expressing GABA neurons (Figure 1b–c). The mechanical stability of the optetrode assembly combined with the thin, flexible tetrode wires allowed us to isolate single units (Figure 1d) and hold them for many weeks, according to a conservative, objective statistical standard (Figure 1e–f). With this approach, we could measure auditory responsiveness and local inhibitory tone from individual RS neurons in awake, head-fixed adult mice over a 7–8 week period surrounding varying degrees of auditory nerve injury (Figure 1g). Although we could occasionally isolate PV-expressing FS interneurons on our tetrodes (Figure 1b–c), we could rarely hold these neurons for more than a single recording session (refer to Figure 1—figure supplement 1). Therefore, all descriptions of long-term changes in single unit response properties were limited to RS, putative pyramidal neurons.

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Most forms of cochlear injury induce an intractable set of changes to the auditory nerve as well as sensory and non-sensory cells within the cochlea. In cases of widespread cochlear damage, it is impossible to attribute abnormal cortical tuning to a central plasticity versus abnormal cochlear filtering or amplification. We circumvented this problem by selectively eliminating afferent nerve fibers without permanently affecting cochlear mechanics using a well-characterized noise exposure protocol that lesions approximately 50% of high-frequency afferent nerve synapses in the 16–45 kHz region of the cochlea without damaging hair cells (n = 4, Figure 2a) (Wan et al., 2014; Kujawa and Liberman, 2009). This protocol induces only a temporary elevation of the auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) thresholds, but a permanent reduction in ABR wave 1 amplitude, which has been shown to reflect the permanent elimination of high-frequency cochlear afferent synapses (Figure 2b, the reader is referred to the figure legends and Supplementary file 1 for most statistical reporting) (Liberman and Kujawa, 2017).

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We implanted optetrode assemblies into the 32 kHz region of the A1 tonotopic map and recorded RS units with high-frequency receptive fields, low-intensity thresholds to broadband noise stimulation and strong feedforward inhibition from PV neurons (Figure 2c–e, top row). Several hours after noise exposure that affects high-frequency regions of the cochlea, the same unit exhibited elevated response thresholds for a broadband noise burst, slightly reduced PV-mediated inhibition and the appearance of a new, well-tuned low-frequency receptive field that was absent just hours earlier (Figure 2c–e, second row). We quantified the invasion of spared, low-frequency inputs and the eventual restoration of the original receptive field by measuring daily changes in frequency response area (FRA) overlap with the baseline FRA as well as tone-evoked firing rates from the spared (4–6 kHz) and partially denervated (32–48 kHz) cochlear regions (Figure 2f, left). We compared these metrics of receptive field reorganization against the typical biomarkers of hyperexcitability in the auditory pathway: decreased response thresholds, increased spontaneous firing rate and increased gain, defined here as the slope of the stimulus input-output function (Figure 2f, middle). Finally, we related these markers of RS unit hyperexcitability and receptive field plasticity to changes in the strength of PV-mediated inhibition (Figure 2f, right; n = 208).

Several hours after noise exposure, firing rates evoked by stimulation of spared, low-frequency cochlear regions had nearly doubled (increased by 96.7%, p=0.04) with a small, but significant decrease in inhibition (−9.8%, p=0.02) and no significant change in gain or spontaneous rate (Figure 2g). Six to ten days after noise exposure, inhibition had decreased by 40% (p<0.0001), receptive fields remained focused on spared regions of the cochlea (p<0.01) and spontaneous firing rate was significantly elevated (p<0.05). Central gain, spontaneous firing rate and frequency tuning all shifted back towards baseline values as response thresholds in the cochlea, ABR and cortical neurons recovered to pre-exposure levels. By the time of the final recording session, approximately 7 weeks after noise exposure, reduced PV-mediated inhibition (−19%, p<0.001) was the only enduring compensatory plasticity marker for the putative loss of high-frequency auditory nerve synapses.

Exposure to ototoxic drugs can cause a sudden and extreme loss of afferent signaling from the cochlea. Would homeostatic adjustments support as complete a recovery of function following a massive loss of auditory nerve fibers? We addressed this question by applying ouabain bilaterally to the cochlear round window membrane (Figure 3a). In mice, ouabain selectively and evenly eliminates >95% of Type-I spiral ganglion afferent neurons across the frequency map, without affecting other types of sensory and non-sensory cells in the cochlea or auditory nerve (Yuan et al., 2014). Bilateral ouabain treatment virtually eliminated the ABR without any adverse DPOAE effects in all mice (n = 6, Figure 3b), but, interestingly, was associated with a slow, partial recovery of sound-evoked cortical spiking in half the mice (Figure 3c) but an unremitting loss of auditory responsiveness in the other half (Figure 3d).

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When DPOAE thresholds are normal, ABR wave 1b amplitude is an accurate proxy for the number of cochlear afferent synapses (Wan et al., 2014; Kujawa and Liberman, 2009; Liberman and Kujawa, 2017). However, the ABR wave 1b amplitude was not significantly different between mice that recovered auditory processing following ouabain treatment versus those that did not (unpaired t-test, p>0.4; see also Figure 3—figure supplement 1). Whereas our estimate of peripheral denervation bore no relationship to the mode of cortical recovery, early dynamics in inhibitory tone and spontaneous firing rate were linked to the recovery of cortical processing. RS units that eventually recovered auditory thresholds exhibited a transient spike in spontaneous firing rate, a sustained increase in central gain and a steep drop in PV-mediated inhibition that began to recover as high-threshold sound-evoked activity returned (Figure 3e–h, top row, n = 156). By contrast, in RS units that never recovered auditory sensitivity, changes in spontaneous rate were comparatively sluggish, while inhibitory strength declined gradually and monotonically (Figure 3e–h, middle row, n = 169). This stark dichotomy in the cortical response to nerve injury was shared among all units recorded from a given mouse; if one unit recovered auditory responsiveness, all units recovered auditory responsiveness (Figure 4). As a negative control in a separate group of mice (n = 3), we applied sterile water to the round window membrane rather than ouabain and confirmed that cortical response properties were stable over the recording period in mice with intact auditory nerves (Figure 3e–h, bottom row, n = 156).

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These findings highlight the coordination of short- and long-term changes in adult A1 following peripheral nerve injury. Spontaneous rate, central gain and inhibition all scaled with the degree of nerve damage (Figure 3f–h versus Figure 2g, Figure 4), but varied substantially both over time and between mice. Restored auditory sensitivity was associated with a sharp loss and partial recovery of inhibition from PV interneurons, where the degree of eventual recovery could be predicted from changes in inhibition ~1 week after nerve damage (Figure 4a). Not only was PV-mediated inhibition a predictor of sensory recovery for both mild and severe peripheral damage, but also it was a better predictor than were modifications in spontaneous activity (Figure 4b) or central gain, the biomarkers most commonly employed to assess central auditory plasticity following sensorineural hearing loss (refer to Figure 4—figure supplement 1 for an expanded analysis of predictors of recovery).

In this study, we tracked a plasticity in PV-mediated inhibition and single neuron responsiveness in the primary auditory cortex of adult mice following a sudden loss of input from the auditory nerve. Just hours after noise exposure, we observed the appearance of new, low-threshold receptive fields tuned to undamaged regions of the cochlea, accompanied by a small, significant drop in PV-mediated inhibition. Over the ensuing weeks, as cochlear thresholds and cortical receptive field tuning returned to baseline conditions, we noted only a brief spike in traditional biomarkers of central auditory hyperactivity, such as increased spontaneous firing rate and increased central gain. By contrast, PV-mediated inhibition remained reduced through our final recording session and was the sole physiological indicator for the permanent, presumed loss of high-frequency cochlear synapses. Importantly, this is not to say that auditory response normalization was mediated by disinhibition; our observations are correlative and do not speak to the necessity nor sufficiency of changes in PV networks for functional recovery. Compensation for peripheral damage could have arisen from post-synaptic changes in GABA receptors in the RS principal neurons recorded here (Sarro et al., 2008) or from presynaptic changes in the GABA neurons themselves (Marik et al., 2014; Keck et al., 2011; Hengen et al., 2013), as well as many other homeostatic plasticity mechanisms in the RS neurons including upward scaling of glutamatergic synapses (O'Brien et al., 1998; Turrigiano et al., 1998), changes in extrasynaptic GABA or glutamate receptors that mediate tonic currents (Chen et al., 2010; Fleming et al., 2011; Sametsky et al., 2015), or changes in intrinsic membrane response properties (Turrigiano et al., 1994; Karmarkar and Buonomano, 2006; Li et al., 2015).

In classic and contemporary studies of adult cortical plasticity following deafferentation, fine-scale reorganization varied widely between local subnetworks of RS neurons and the completeness of global remapping was negatively correlated with the spatial extent of peripheral lesions (Robertson and Irvine, 1989; Merzenich et al., 1984; Barnes et al., 2015; Keck et al., 2008). Here, we report that the mode of cortical sensory recovery (complete, partial or none) was roughly shared between all RS units recorded in a given mouse and did not strictly depend on the estimated auditory nerve damage. Unlike focal ablations of the retina, basilar membrane or skin surface, cochlear ouabain treatment eliminates 95% of primary afferent synapses without affecting sensory transduction mechanisms (Chambers et al., 2016; Yuan et al., 2014). This provided us with an uncommon opportunity to track the restoration of sensory responses transmitted through the small fraction of surviving nerve fibers, rather than the typical approach of describing competitive reorganization from ectopic, spared inputs neighboring the lesion. As compared to the rapid unmasking of excitatory inputs from neighboring undamaged regions of the sensory organ, which occurs within hours (Figure 2, see also [Gilbert and Wiesel, 1992; Calford and Tweedale, 1988]), the recovery of function for spared afferent inputs interspersed within a damaged portion of the nerve, if it occurred at all, unfolded over several weeks. The variable modes of recovery between mice with carefully matched nerve damage may relate to earlier observations that cortical sensory reorganization is not only determined by the pattern and density of peripheral innervation, but may also be directed by activity-dependent differences that are orchestrated through behavioral use (Clark et al., 1988; Xerri et al., 1998; Polley et al., 1999).

Following either type of nerve damage, the cortical networks that recovered function were those that matched the sudden drop in bottom-up excitatory drive with a rapid dip in PV-mediated inhibition. Precisely balanced excitation and inhibition enables a wider dynamic range of sensory information coding (Isaacson and Scanziani, 2011; Shadlen and Newsome, 1998; Pouille et al., 2009; Zhou et al., 2014) and supports adaptive plasticity without forsaking network stability (Vogels et al., 2011; Froemke et al., 2013; Hellyer et al., 2016; Barrett et al., 2016). These findings suggest that self-regulating PV circuits may not only play an important role in rebalancing network activity in response to reduced afferent drive during developmental critical periods (Xue et al., 2014; Yazaki-Sugiyama et al., 2009), but in the adult cortex following sensory nerve damage as well.

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Author details

1. Jennifer Resnik

   1. Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, United States
   2. Department of Otolaryngology, Harvard Medical School, Boston, United States

   Contribution

   JR, Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Writing—original draft, Writing—review and editing

   For correspondence

   Jennifer_Resnik@MEEI.HARVARD.EDU

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-0573-0008

2. Daniel B Polley

   1. Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary, Boston, United States
   2. Department of Otolaryngology, Harvard Medical School, Boston, United States

   Contribution

   DBP, Conceptualization, Funding acquisition, Methodology, Writing—original draft, Project administration, Writing—review and editing

   For correspondence

   Daniel_Polley@meei.harvard.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-5120-2409

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