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bioRxiv · 10.1101/2025.07.09.663954

Cell-type-specific plasticity in synaptic, intrinsic, and sound response properties of deep-layer auditory cortical neurons after noise trauma

Zhao, Y.·Kouvaros, S.·Schneider, N. A.·Krall, R. F.·Lam, S.·Arnold, M. P.·Williamson, R. S.·Tzounopoulos, T.
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Abstract

Peripheral trauma, such as noise-induced hearing loss (NIHL), triggers compensatory plasticity in the auditory cortex (ACtx) to maintain auditory function. While cortical plasticity in superficial cortical layers has been relatively well studied, the plasticity mechanisms governing deep-layer excitatory projection neurons remain less understood. Here, we investigated the plasticity of layer (L)5 extratelencephalic (ETs) and L6 corticothalamic neurons (CTs) following NIHL. Using a combination of in vitro slice electrophysiology, optogenetics, and in vivo two-photon imaging in a mouse model of NIHL, we characterized changes in evoked thalamocortical (TC) synaptic input strength, intrinsic excitability, and sound response properties. We found that TC input was initially equivalent between ETs and CTs, then shifted to CT-dominant one day after noise exposure. This shift renormalized to equivalent seven days after noise exposure and was associated with a transient increase in both the quantal size (q) in TC[->]CT synapses and intrinsic CT suprathreshold excitability. ETs maintained stable intrinsic properties and showed minor changes in their TC input. In vivo imaging revealed that CTs displayed a persistent elevation in sound intensity thresholds, whereas ETs transiently shifted their best frequency representation and reduced their responsiveness to high-frequency tones one day after NIHL, followed by recovery at seven days. Together, our findings highlight cell-type-specific plasticity mechanisms in deep-layer cortical neurons, enhance our understanding of cortical adaptation to peripheral damage, and highlight targets for developing therapeutic strategies to mitigate hearing loss and related disorders such as tinnitus and hyperacusis. Short AbstractPeripheral damage drives auditory cortex (ACtx) plasticity, but the underlying synaptic and cellular mechanisms remain poorly understood. We used a combination of in vitro slice electrophysiology, optogenetics, and in vivo two-photon imaging to investigate layer 5 extratelencephalic (ET) and layer 6 corticothalamic (CT) neuronal plasticity in mice, following noise-induced hearing loss (NIHL). Thalamocortical (TC) input was initially balanced between CTs and ETs but shifted to CT-dominant one day post-NIHL and then normalized by day seven. This transient shift was accompanied by increased quantal size and suprathreshold excitability in CTs, with minimal changes in ETs. In vivo, CTs exhibited persistent elevation in sound intensity thresholds, while ETs showed a transient shift in frequency tuning and reduced high-frequency responsiveness that recovered within a week. These findings reveal distinct, cell-type-specific plasticity mechanisms in deep-layer ACtx neurons following peripheral damage and highlight potential targets for treating hearing loss-related disorders such as tinnitus and hyperacusis.

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Zhao, Y., Kouvaros, S., Schneider, N. A., Krall, R. F., Lam, S., Arnold, M. P., Williamson, R. S., Tzounopoulos, T.. 2025-07-14. Cell-type-specific plasticity in synaptic, intrinsic, and sound response properties of deep-layer auditory cortical neurons after noise trauma. https://doi.org/10.1101/2025.07.09.663954

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