Journal club: Impact of enhanced/reduced medial olivocochlear (MOC) input on the noise-susceptibility of the developing cochlea.

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Today's journal article

Castagna VC, Boero LE, Di Guilmi MN, Catalano Di Meo C, Ballestero JA, Fuchs PA, Lauer AM, Elgoyhen AB, Gomez-Casati ME. Strengthening Medial Olivocochlear Feedback Reduces the Developmental Impact of Early Noise Exposure. 

Why I picked this article

Most people think of hearing loss as a disease of old age. However, the inner ear is especially vulnerable when hearing first begins. Likewise, the developing central auditory system in the brain is also vulnerable during development, as neurons in the brain are actively forming synapses for auditory processing. 

There is a critical milestone in the development of hearing called the "hearing onset", which in mice is around 12-14 days after birth. The week before the hearing onset, auditory hair cells and their synapses are maturing, auditory nerve fibres are wiring up, and brain circuits are tuning themselves.

This research explores how a neuronal feedback pathway from the brainstem, the medial olivocochlear (MOC) system, influences the cochlea during this sensitive period. MOC synapses use acetylcholine as the neurotransmitter to dampen activity in hair cells. In the mature cochlea, the MOC neurons form synapses with outer hair cells (OHCs) to adjust the sensitivity of the cochlea and protect the cochlea from noise. However, during development, MOC neurons also form synapses with inner hair cells (IHCs). This research explores the impact of the cholinergic input from MOC neurons on the development of the cochlea and any protection from noise. 

Some of the research findings

Animal Model: 
  • Two well-established genetically modified mice were used: 
    • α9 knockout (α9KO) = in these mice, the cholinergic input from MOC neurons is not received by hair cells due to the lack of α9 acetylcholine receptors.
    • α9 knock-in (α9KI) = α9KI mice carrying an α9 nAChR subunit point mutation that enhances responses to ACh. The effect of cholinergic input from MOC neurons is enhanced in hair cells due to an increase in the α9 acetylcholine receptors.
    • Backcrossed to FVB.129P2-Pde6b+ Tyrc-ch/AntJ mice. 
    • Both sexes; no sex differences reported. 
    • Ages studied P12–P75.
  • Noise exposure: 
    • single 1 h broadband exposure (1–16 kHz) at 100 dB SPL under anesthesia at P15 (~hearing onset).
Outcome measures: 
  • ABR and ABR wave I amplitude (5.6–45.25 kHz tone pips)
  • DPOAE (2f1–f2, f2/f1=1.2) - to assess the outer hair cell (OHC) function. 
  • Ribbon synapse counting:
    • CtBP2 (presynaptic, mouse anti-CtBP2 IgG1; BD Biosciences, San Jose, CA; Cat#612044, RRID:AB_399431, 1:200)
    • GluA2 (postsynaptic, mouse anti-GluA2 IgG2a; Millipore, Billerica, MA; Cat#MAB397, RRID:AB_11212990, 1:2000) immunolabels. 
    • confocal acquisition and automated counting (https://github.com/vcastagna/CountsSynapses).
Auditory function in developing animals:
  • Control: hearing thresholds around 50-60 dB SPL at P14
  • α9KO (weak/absent MOC): lower hearing thresholds (35-40 dB SPL), higher amplitudes at P14
  • α9KI (strong MOC): higher thresholds at 70-75 dB SPL and lower amplitude at P14
  • The difference was frequency dependent (more prominent at 16kHz +) and developmental stage dependent. 
Auditory function after noise exposure: 
After noise-exposure at P15, animals were monitored until P75. 
  • Control: ABR thresholds were unchanged at 1 day but were elevated across 8–22.65 kHz at 7 days, and the shift persisted to 2 months (P75). 
    • ABR wave I amplitudes fell at 1 day and remained significantly depressed at 7 days and 2 months, indicating sustained neural compromise. DPOAE thresholds rose transiently at 16 kHz at 7 days, then normalized by 2 months.
  • α9KO (weak/absent MOC): thresholds increased at 7 days (8 and 16 kHz) but largely recovered by 2 months.
    • DPOAE at 16 kHz and ABR wave I amplitudes showed lingering deficits, consistent with lasting neural stress despite partial threshold recovery.
  • α9KI (strong MOC): thresholds and DPOAEs remained stable at all time points; no functional hit was detected after the same noise.
From part of Fig3C. Hearing thresholds of the α9KI control group and α9KI noise-exposed mice are nearly identical (22.65kHz, high frequency). Castagna et al. 2025. 

Ribbon synapses in the cochleae of 2-month-old mice baseline: 
  • Synapse number per inner hair cell (IHC) was: Control > α9KI/α9KO at P14 across all frequency zones. Similar but slightly different trends at 2-month-old. 
  • CtBP2 size was: Control >  α9KI/α9KO in the low frequency zone, α9KO > Control > α9KI in the high- and mid-frequency zone at both P14 and 2-month-old. 
  • GluA2 size was α9KO > Control >= α9KI as the general trend was more evident at 2-month-old. 
Ribbon synapses in the cochleae of 2-month-old mice after noise exposure: 
  • Control:  exposed ears showed significant inner hair cell synapse loss at apex and base: putative ribbon synapses were reduced by about 34% (apex) and 33% (base); presynaptic ribbons (CtBP2) dropped up to 37% basally; GluA2 patches also declined in both regions.
  • α9KO-exposed ears also lost synapses, though to a lesser extent depending on cochlear region (e.g., ribbon puncta −14.7% apex, −24.8% base; synapse counts −26.2% apex, −25.9% base).
  • α9KI-exposed ears showed no significant synapse loss in any region; a modest, non-significant ~19% increase in basal synaptic density was observed.
Taken together, the cochleae of the hearing onset age were susceptible to noise-induced damage; however, enhanced MOC feedback shields the auditory system from noise damage during this period.

Haruna's takeaway

What a cool paper! The parallel use of two genetically modified mouse models to have gain-of-function (α9KI) and loss-of-function (α9KO) of cholinergic neurotransmission is a very clear design to see the impact of cholinergic transmission in the cochlea. It highlights the significance of the transient, time-limited MOC synapses on the inner hair cells. It seems so powerful that just by enhancing the cholinergic signalling, the damage from noise exposure becomes minimised. The postnatal developmental stage is so interesting and dynamic, and I would love to learn more about this age group and how different components (immune cells, endocochlear potential and vascular development) also play integrated roles during the maturation process. 

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This is Haruna's 97/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.