Neurons in sensory cortex exhibit a remarkable capacity to maintain stable firing rates despite large fluctuations in afferent activity levels. However, sudden peripheral deafferentation in adulthood can trigger an excessive, non-homeostatic cortical compensatory response that may underlie perceptual disorders including sensory hypersensitivity, phantom limb pain, and tinnitus. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic two-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of spatially diffuse hyperactivity, hyper-correlation, and auditory hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles also displayed hypersensitive decoding of spared mid-frequency tones that mirrored behavioral hypersensitivity, suggesting that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may be an underlying source of auditory hypersensitivity. Excess cortical response gain after acoustic trauma was expressed heterogeneously among individual PyrNs, yet 40% of this variability could be accounted for by each cell’s baseline response properties prior to acoustic trauma. PyrNs with initially high spontaneous activity and gradual monotonic intensity growth functions were more likely to exhibit non-homeostatic excess gain after acoustic trauma. This suggests that while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where indicators of reduced inhibition can presage pathological hyperactivity following sensorineural hearing loss.
Throughout the brain, neurons exhibit a remarkable capacity to maintain stable firing rates despite large perturbations in afferent activity levels. As an exception, homeostatic regulation of neural activity often fails in the adult auditory system after hearing loss. Cochlear deafferentation caused by aging or noise exposure triggers widespread neural hyperactivity, particularly in the auditory cortex (ACtx), which underlies perceptual disorders including tinnitus and hyperacusis. Here, we show that mice with noise-induced damage of the high-frequency cochlear base were behaviorally hypersensitive to spared mid-frequency tones and to direct optogenetic stimulation of auditory thalamocortical neurons. Chronic 2-photon calcium imaging from ACtx pyramidal neurons (PyrNs) revealed an initial stage of diffuse hyperactivity, hypercorrelation, and hyperresponsivity that consolidated around deafferented map regions three or more days after acoustic trauma. Deafferented PyrN ensembles displayed hypersensitive decoding of spared mid-frequency tones, mirroring behavioral hypersensitivity. At the level of individual PyrNs, some exhibited stable, homeostatic gain control after acoustic trauma, while others showed non-homeostatic excess gain. Interestingly, factors such as baseline spontaneous activity levels and sound level encoding could account for 40% of the variability in PyrN gain regulation after acoustic trauma. These findings suggest that non-homeostatic regulation of cortical sound intensity coding following sensorineural loss may underlie the well-established clinical phenomenon of loudness hypersensitivity. Further, while cortical gain changes are triggered by reduced bottom-up afferent input, their subsequent stabilization is also shaped by their local circuit milieu, where baseline response features can identify neurons with the greatest propensity for developing pathological hyperactivity following sensorineural hearing loss.
Sound perception is closely linked to the spatiotemporal patterning of neural activity in the auditory cortex (ACtx). Inhibitory interneurons sculpt the patterns of excitatory ACtx pyramidal neuron activity, and thus play a central role in sculpting the perception of sound. Reduced inhibition from parvalbumin-expressing (PV) inhibitory interneurons and the associated increased gain of sound-evoked pyramidal neuron spike rates are well-established consequences of aging and sensorineural hearing loss. Here, we reasoned that changes in PV-mediated inhibition would directly impact the perception of loudness. We hypothesized that ACtx PV activity could function as a perceptual volume knob, where reduced or elevated PV activity would increase or decrease the perceived loudness of sound, respectively. To test these hypotheses, we developed a two-alternative forced-choice loudness classification task for head-fixed mice and demonstrated that noise-induced sensorineural hearing loss directly caused a ~10 dB loudness hyperacusis that begins hours after noise-induced sensorineural hearing loss and persists for at least several weeks. Conversely, sounds were perceived as ~10 dB softer during optogenetic activation of ACtx PV neurons without having any effect on the overall detectability of sound. These data suggest that ACtx PV neurons can bi-directionally control the perceived loudness of sound, presumably via the strength of their inhibition onto local pyramidal neurons. Further, these data identify cortical PV neurons as a target for hyperacusis therapies and demonstrate a direct link between acquired sensorineural hearing loss and loudness hyperacusis.
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